2024 March

  • Neither the cause of autism nor the effects of cannabis on a developing fetus are entirely clear 
  • Researchers at the Ottawa Hospital and University of Ottawa studied 2,200 Canadian women who reported using marijuana while pregnant 
  • The rate of autism among their children was four per 1,000 person-years, compared to 2.42 among children whose mothers did not use marijuana  

Pregnant women who smoke cannabis almost double the risk of their baby being born autistic, warns a new study.

In the largest ever study of its kind, researchers found that children whose mothers reported using cannabis during pregnancy were at greater risk of autism.

The incidence of autism was four per 1,000 person-years among children exposed to cannabis in pregnancy, compared to 2.42 among unexposed children.

‘There is evidence that more people are using cannabis during pregnancy,’ said senior study author Professor Mark Walker, of the University of Ottawa in Canada.

‘This is concerning, because we know so little about how cannabis affects pregnant women and their babies.

‘Parents-to-be should inform themselves of the possible risks, and we hope studies like ours can help.’

A Canadian study found that rates of autism were twice as high among the children of women who used marijuana during pregnancy, compared to rates among children of mothers  who did not use the drug (file)

The researchers reviewed data from every birth in Ontario between 2007 and 2012, before recreational cannabis was legalised in Canada.

Of the half a million women in the study, about 3,000 (0.6 per cent) reported using cannabis during pregnancy.

Importantly, these women reported using only cannabis.

The team had previously found that cannabis use in pregnancy was linked to an increased risk of premature birth.

In that study, they found that women who used cannabis during pregnancy often used other substances including tobacco, alcohol and opioids.

Considering those findings, in the current study the researchers specifically looked at the 2,200 women who reported using only cannabis during pregnancy, and no other substances.

The findings, published in the medical journal Nature Medicine. showed that babies born to this group still had an increased risk of autism compared to those who didn’t use cannabis.

The researchers do not know exactly how much cannabis the women were using, how often, at what time during their pregnancy, or how it was consumed.

But as cannabis becomes more socially acceptable, doctors are concerned that some parents-to-be might think it can be used to treat morning sickness.

Dr Daniel Corsi, an epidemiologist at The Ottawa Hospital, said: ‘In the past, we haven’t had good data on the effect of cannabis on pregnancies.’

He added: ‘This is one of the largest studies on this topic to date.

‘We hope our findings will help women and their health-care providers make informed decisions.’

Autism is fairly common, but still poorly understood.

In the US, about one in every 59 children born will fall somewhere on the autism spectrum.

About one in every 66 children in Canada are autistic and, globally, the rate is approximately one in every 160 children.

Research suggests that there is likely some genetic basis for autism,  which is about four-times more common among boys than girls.

But scientists believe exposures in the womb likely play a role as well.

The effects of cannabis are similarly poorly understood to the origins of autism.

Although doctors caution against it, cannabis use has not been linked to miscarriages in humans (though animal studies have suggested an increased risk) and evidence on the link between weed and low birth-weight is mixed.

Marijuana use during pregnancy has been linked, however, to up to 2.3 times greater risks of stillbirth.

The Ottawa Hospital study did not investigate how exactly marijuana use in pregnancy might lead to autism in a child, but scientists believe that the drug’s interaction with the so-called endocannabinoid system within the nervous system could play a role in the development of the behavioral condition.

By NATALIE RAHHAL ACTING US HEALTH EDITOR

Source: Autism is twice as common in children whose mothers used cannabis in pregnancy | Daily Mail Online

PUBLISHED 17:13, 10 August 2020

Filed under: Cannabis/Marijuana,Drug use-various effects,Drug use-various effects on foetus, babies, children and youth,Health :

Cannabis use during pregnancy is associated with a host of negative outcomes.

Sondem/AdobeStock

The recent paper by Stanciu discussing cannabis use in pregnancy1 makes several useful and highly salient points. With a more complete understanding of the published literature further important patterns in the data emerge. They aid our understanding of the pathobiology of in utero cannabis exposure and thereby powerfully inform the community on the most appropriate manner in which to regulate cannabis and cannabinoids from an improved evidence base.

It is well known that cannabis use has been liberalized across the United States as a result of well-financed and orchestrated campaigns.2 Stanciu is correct that most epidemiological studies point towards harmful associations, that cannabis use in pregnancy is becoming more common, that it is widely recommended in pregnancy by cannabis dispensaries, and that increased rates of low birth weight, premature and stillbirths, and increased neonatal intensive care admission are well recognized associations. It is correct that all 4 longitudinal studies of children born after prenatal cannabis exposure (PCE) show increased adverse neurodevelopmental outcomes including impaired executive function, visuomotor processing deficits, heightened startle responses, impulse control, heightened susceptibility to addiction in later life, emotional behaviors, and motor defects.3-5 Well-documented impacts on the glutamatergic, GABAergic and dopaminergic signaling in the brain are of concern as they represents major neurotransmitters in the central nervous system [CNS]. Well-established links between cannabis use and schizophrenia, bipolar disorder, anxiety, depression, and suicidal ideation are also correctly described. It is true that ACOG have made both historical and recent recommendations against its use in pregnancy, and these recommendations are relevant to practice in all medical specialties.

Conceptual and epidemiological extensions

While it is correct to observe that there is no described phenotype following PCE, it is also important to note that many of these neurodevelopmental deficits have been noted to overlap the ADHD and autism spectrum disorders. This is likely epidemiologically highly significant for the US, where autistic spectrum disorders have been shown to be growing exponentially.6 Cannabis use across the US was shown to be independently associated with autism rates across both time and space, to be dose-related6, and, based on conservative projections, has been predicted to be at least 60% higher in cannabis-legal states than in states where cannabis was illegal by 2030.7

A large Hawaiian study found an increased incidence of microcephaly (R.R. = 12.80, 95%C.I. 4.13-36.17)8 and the CDC have twice reported elevated rates of anencephalus (adjusted O.R. 1.7, C.I. 0.9-3.4) and (posterior O.R. 1.9 (C.I. 1.1, 3.2).9,10 This sets up a clear spectrum of severity from mild neurodevelopmental impairment, to microcephaly, to anencephalus and then fetal death. In the context of dose-response relationships and strong geotemporospatial associations issues of causality necessarily arise.

Stanciu’s observation that preclinical studies in experimental animals are important to understand the likely effects of PCE in individuals, not least due to the problem of the frequent exposure to multiple substances clinically, is also correct. This issue was studied in detail long ago in the 1960s and 1970s, and succinctly summarized by Graham’s telling observation: “oedema, phocomelia, omphalocoele, spina bifida, exencephaly, multiple malformations including myelocoele. This is a formidable list.”11

However, a reasonable question might be: “Why don’t we see such a broad teratological spectrum clinically?”

Stanciu’s remark that there are “no overt birth defects” is an oft-repeated myth and is in error, as well as obviously being at odds with several preclinical studies, especially in the most predictive species for human teratology (ie, hamsters and white rabbits).12,13

A recent paper from the Centers for Disease Control (CDC) noted that 4 defects, anencephalus, gastroschisis, diaphragmatic hernia and esophageal atresia were more common following PCE.9 The American Academy of Pediatrics (AAP) and the American Heart Association (AHA) issued a joint position statement that both ventricular septal defect (VSD) and Ebsteins anomaly were also elevated by PCE.14

The review of 17 years of birth defects from Hawaii found 21 defects to be elevated after PCE and featured prominently cardiovascular defects (atrial septal defect (ASD), VSD, hypoplastic left heart syndrome, tetralogy of Fallot (ToF) and pulmonary valve atresia or stenosis), chromosomal defects such as Downs syndrome, body wall defects such as gastroschisis, limb defects including syndactyly and upper limb reduction defects, facial, bowel and genitourinary system defects with calculated rate ratios ranging from 5.26 (C.I. 1.08-15.46) to 39.98 (C.I. 9.03-122.29).8

In September and October 2018 Colorado released 2 datasets of congenital anomalies across the period of its cannabis legalization program from 2000 to 2013 and 2000 to 2014 and reported 87,772 and 64,463 major defects respectively (which are obviously contradictory).15 Based on 4830 and 4026 major anomalies in the year 2000 this represents a case excess of 20,152 (29.80%) or 11,753 anomalies (22.30%) respectively. During this period the use of tobacco and alcohol was declining and other drug use was not rising. Only cannabis use rose. Importantly, models quartic in time indicated a non-linear response of total birth defects to rising cannabinoid exposure. Estimated exposure to several cannabinoids including cannabinol, THC, and tetrahydrocannabivarin was shown to be positively associated with major defect rates and to be robust to adjustment for other drug use. CNS defects (microcephalus, neural tube defects), cardiovascular defects (ASD, VSD, patent ductus arteriosus (PDA)), total chromosomal anomalies including Downs syndrome, musculoskeletal, respiratory and genitourinary anomalies all rose dramatically.

Defects described as being cannabis-related (by the Hawaiian, CDC, AAP and AHA investigators) rose more quickly than cannabis-unrelated defects (P<0.003). As fetal cardiac tissue and the central great vessels have high numbers of cannabinoid receptors from early in fetal life it is easy to understand why this pattern might emerge. Since ASD, VSD and PDA are the most common cardiovascular congenital anomalies it is understandable that total cardiovascular anomalies increased in Colorado.

A recent review of total congenital anomalies in Canada showed that they were 3 times more common in the northern territories which consume more cannabis, and that these effects were robust to adjustment for other drug exposure and for socioeconomic variables.16 Total cardiovascular defects, Downs syndrome and gastroschisis were noted prominently in this series. Neural tube defects including anencephalus and spinal bifida and meningomyelocoele were falling across Canada from 1991 to 2007, although it was not clear whether the decline was due to dietary folate supplementation or increased antenatal early termination of pregnancy for anomalies (ETOPFA).17 Notwithstanding this it was recently shown that within each of 3 periods (the pre-folate period, the transitional period and the post-folate period) neural tube defects across Canada were becoming more common.17

An Australian dataset found greatly elevated relative rates of cardiovascular (PDA, ASD, VSD, ToF, transposition of great vessels), body wall (gastroschisis, exomphalos, diaphragmatic hernia), chromosomal (Downs syndrome, Turners syndrome, Edwards Syndrome (trisomy 18)), genitourinary, hydrocephalus, neural tube defects, and bowel defects with borderline results for anencephalus (ETOPFA data unavailable) in a high cannabis use area in Northern New South Wales compared to Queensland state-wide data.18

Transposition of the great vessels was previously linked with paternal cannabis exposure.19

The presence of Downs syndrome on the list of cannabis-associated anomalies in Hawaii, Colorado, Canada and Australia is important as it necessarily implies megabase-scale genetic damage.8,15,16,18 Since cannabis interferes with tubulin metabolism and thus the separation of the chromosomes which occurs in mitotic anaphase it is easy to see how PCE-induced chromosomal mis-segregation errors might occur.20 Studies of PCE in rodents show that cannabis induces major alterations of gene expression widely with 8% alteration in DNA sperm methylation patterns, changes which are transmissible to subsequent F1 generations.21

Stanciu’s comment about a so-called “cannabis phenotype” is provocative. It is true that a “fetal cannabis syndrome” (FCS) has not been described in the way that a “fetal alcohol syndrome” (FAS) has. Fetal alcohol syndrome of course is a very diverse and pleomorphic group of clinical presentations and a wide spectrum of presentations is described. Importantly the fetal alcohol has been described as being mediated by the cannabinoid type 1 receptor (CB1R’s) and is mediated epigenetically.22-26 The suggestion that alcohol can work epigenetically via CB1Rs but cannabinoids cannot defies the bounds of credulity. Moreover, as noted above, there is as yet no objective marker of gestational cannabinoid exposure. Once such a biomarker has been derived (say epigenetically and / or glycomically27) then an objective measure will exist to allow genotype-epigenotype-phenotype correlative studies to be performed so that we can usefully investigate if a fetal cannabis syndrome phenotype spectrum might exist. However, if researchers do not believe it might exist then it is clear that one will not be described. It is our view that once an objective biomarker is established it will only be a matter of time before a diverse and highly variable FCS is also defined and enters the clinical diagnostic compendium.

Recent US data and analysis

CDC publish 5-year averaged birth defect data for many states as part of the National Birth Defects Prevention Network (NBDPN) annual reports which can be combined with Substance Abuse and Mental Health Services Administration (SAMHSA) state and substate data to examine nationwide drug-related trends. ETOPFA rates are taken from historical time series.

Figure 1A charts Downs syndrome rates corrected for estimated ETOPFA rates against cannabis exposure. Both rates are elevated (shown as pink and purple) in Colorado, Oregon, Washington, Alaska, Maine and Massachusetts.

Downs Syndrome By Cannibas Use

Figure 1B shows the relationship of Downs syndrome to cigarette use for this year which is very different.

Downs Syndrome By Cigarette Use

The Figure also shows the Downs syndrome rates by cannabis use quintile for both the raw Downs syndrome rates (Figure 1C) and the ETOPFA-corrected data (Figure 1D). One notes not only a rising trend with cannabis use, but also an abrupt jump from the fourth to the fifth quintile.

Downs Syndrome Rate by Quintiles of Cannabis Use

This jump is seen when many defects are analyzed in this manner. A list of defects would include, but would not be limited to: atrial septal defect, atrioventricular septal defect, cleft lip and / or palate (all forms combined), trisomy 21 (Downs syndrome), Turners syndrome and ventricular septal defect.

Downs Syndrome by Quintiles of Cannabis Use (ETOPFA-CORRECTED)

Figure 2 lists the prevalence ratio of 62 congenital anomalies tracked by the National Birth Defect Prevention Network (NBDPN) in quintile 5 versus lower quintiles and notes that 44 of them are significantly elevated in the highest quintile of cannabis using states.

Prevalence Ratios

Literature-wide limitations

It should be noted in passing that most of these studies suffer from several major common limitations. Many of the defects described are disorders for which ETOPFA is commonly practiced and frequently recommended to pregnant patients. ETOPFA data was generally not available to investigators. It is beyond question that were such data included the findings would be of greater magnitude and of even greater concern. Secondly many studies rely on self-report which is subject to recall-bias and may be misled. Patients who use cannabis early in pregnancy but stop after they are informed of their pregnant status might answer “no” to questions of PCE, but in fact their fetus is exposed prenatally due to the prolonged terminal half-life of excretion of cannabinoids from body fat stores. Hence a reliable biomarker is required to properly define the denominator in these studies, but it is not thought to exist at present. It could however easily be derived from epigenomic and/or glycomic studies.27

Thirdly there are major analytical limitations of the described series. Advanced analytical methods that allow data analysis simultaneously across both space and time exist and are called geospatial or spatiotemporal techniques. The CDC has demonstrated ability to track congenital anomalies by county. Application of geospatial techniques to county data is therefore possible and would be well assisted by the provision of cannabis-exposure data from the SAMHSA 395 substate areas. Methods which allow the investigation of apparently causal relationships, including inverse probability weighting and the calculation of E-values to quantify unmeasured confounding have similarly not been deployed in this field.

These deficits in the literature represent major gaps in our knowledge which may readily be addressed by the application of available techniques to currently extant data and thus vastly augment the evidence base for well-informed policy formulation. Our group is presently addressing this major knowledge gap with a series of papers on these and related subjects utilizing geospatiotemporal regression, the formal techniques of causal inference, and multiple imputation of chained equations to complete CDC data for various congential anomalies and heritable childhood cancers where such data is missing or withheld for specific ethnic minorities.

Extensive presently unpublished analyses from our group extend the United States analyses presented in preliminary and embryonic form in Figure 1 and Figure 2 using geotemporospatial and causal inference techniques with strongly confirmatory results for both state-based spatiotemporal association and in several cases causal links.

Concluding thoughts

In broad overview the patterns which emerge from these major population-based studies of cannabis-related human teratology indicate several findings that are remarkable for their consistency across series originating from Hawaii, Colorado, Canada, and Australia and for their exact and precise concordance with very worrying data in experimental animals. Prominent amongst affected organ systems includes the CNS, CVS and chromosomal disorders. Body wall and limb defects also likely follow the endovascular cannabinoid receptor distribution pattern, and this is consistent with current understandings related to the pathogenesis of gastroschisis and limb embryogenesis which are both thought to be primarily vasculocentric. Similarly, in the genitourinary and gastrointestinal systems, peripheral cannabinoid receptors are widely distributed and appear from as early as 12 weeks of fetal life. Dose-response effects are seen in many of the above analyses which is one of the major criteria of Hill’s causal algorithm. The sequence of severity of CNS defects (neurodevelopmental impairments/autism-microcephaly-anencephaly-foetal death) also implies a gradation of phenotypic effects of PCE.

The PCE literature has widespread limitations including its reliance on self-report data, the general non-availability of ETOPFA data, the lack of reliable biomarkers to define exposure, and the pointed absence of state-of-the-art analytical techniques including high-resolution geotemporospatial analysis and the formal techniques of causal inference assessment.

Given these limitations the concordance with preclinical and mechanistic data and the positive and highly consistent associations that have been demonstrated in several jurisdictions are particularly concerning. They carry far-reaching genotoxic and intergenerational implications and argue powerfully against cannabis legalization.

Dr Reece is practice principal at Southcity Family Medical Centre and Professor of Medicine at University of Western Australia and Edith Cowan University. Dr Hulse is Professor of Addiction Medicine within the Division of Psychiatry at The University of Western Australia and the Faculty of Health Sciences at the Edith Cowan University. Neither author has any conflicts of interest to declare.

Source:  https://www.psychiatrictimes.com/view/cannabis-pregnancy-rejoinder-exposition-cautionary-tales   October 2020

Filed under: Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth :

There is evidence in both patients with psychotic disorders and the general population that cannabis use is associated with adverse effects of psychopathology and cognition.

RESEARCH UPDATE

Substance use comorbidity in schizophrenia has been described as “the rule rather than the exception.”1 The large Epidemiological Catchment Area study estimated that 47% of patients with schizophrenia also had a lifetime comorbid diagnosis of a substance use disorder.2 Substance use comorbidity is also often deleterious to the course of schizophrenia, including potential contributions to medication non-adherence and illness relapse.1 Cannabis (marijuana) is one of the most commonly used substances by patients with schizophrenia.

There is recent, renewed interest in the endocannabinoid system, which represents a novel potential treatment target in schizophrenia.3 Modulation of this system by the main psychoactive component in marijuana, Δ9-tetrahydro-cannabinol (THC), can induce acute psychosis and cognitive impairment. However, the non-psychotropic plant-derived agent cannabidiol (CBD) may decrease psychotic symptoms and improve cognitive function in schizophrenia.4-6

Presently, CBD oil is sold at numerous shops throughout the US, with purported benefits that include alleviation of symptoms such as depression, anxiety, insomnia, and pain. However, the purity and safety of CBD is not regulated by the US Food and Drug Administration. CBD may be “contaminated” with some amount of THC and/or other unknown ingredients. In the past decade, there have been a number of systematic reviews regarding associations between cannabis use and psychosis. Therefore, a review of systematic evidence for associations between cannabis use, risk of psychosis, and the clinical course of schizophrenia is of particular relevance to the practicing clinician.

Adverse effects of cannabis on psychosis and cognition

There is evidence from a quantitative review of 15 studies in healthy participants that a single administration of THC (intravenous, oral, or nasal) versus placebo induced positive, negative, and other psychopathology with large effect sizes (ESs).7 Furthermore, evidence from 69 studies, comprising 2152 adolescents and young adults who used cannabis and 6575 controls with minimal cannabis exposure, showed that frequent or heavy use was associated with significantly reduced cognitive functioning with a small-to-medium ES = -0.25, although these effects were diminished with abstinence for more than 72 hours.8

Cannabis use and risk of psychosis

Moore and colleagues9 performed a systematic review of 35 studies of cannabis use and risk of psychotic mental health outcomes. They found that individuals who had used cannabis had a significant, 1.4-fold increased risk of any psychotic outcomes, independent of potential confounding and transient intoxication effects. Findings also provided evidence for a dose-response effect, with even greater, 2.1-fold risk in individuals who used cannabis most frequently.

More recently, Marconi and colleagues10 performed a meta-analysis of 10 studies, including 66,810 individuals, that investigated the association between the degree of cannabis consumption and risk of psychosis. In all individual studies, higher levels of cannabis use were associated with increased risk of psychosis. They also found evidence for a dose-response relationship, with a 2-fold increase in risk for the average cannabis user, and a 4-fold increase in risk for the heaviest users, compared with non-users. Although these findings do not definitively establish a causal association between marijuana use and psychotic disorders, it nevertheless remains a replicated risk factor for psychosis with a clear dose-dependent relationship.

Cannabis use in patients with psychotic disorders

Koskinen and colleagues11 performed a quantitative review of the rates of cannabis use disorders (CUDs) in clinical samples of patients with schizophrenia. They identified 35 studies for inclusion in the meta-analysis. The median current rate of CUD was 16.0% (Interquartile Range [IQR] 8.6-28.6%), and the median lifetime rate of CUD was 27.1% (IQR=12.2-38.5). The rate of current/lifetime CUDs was markedly higher in first-episode (28.6%/44.4%) versus chronic schizophrenia (22.0%/12.2%), as well as in younger patient samples and samples with a high proportion of males. They concluded that approximately 1 in 4 patients with schizophrenia has a diagnosis of a comorbid CUD.

Hunt and colleagues12 more recently performed a systematic review of the prevalence of comorbid substance use in patients with schizophrenia spectrum disorders. They identified 69 studies, and the pooled estimate for current or lifetime CUD was 26.2%. Consistent with the review by Koskinen and colleagues,11 the prevalence was significantly higher in individuals with first-episode psychosis (35.6%) versus chronic schizophrenia (20.8%), but did not differ by study setting or patient clinical status.

The substantial prevalence of cannabis use also appears to extend to the psychosis prodrome. There is evidence from 30 studies, including 4205 individuals at ultra high risk (UHR) for psychosis, that there are high rates of current (26.7%) and lifetime (52.8%) cannabis use, and CUDs (12.8%).13 Compared with non-users, UHR cannabis users also had higher rates of suspiciousness and unusual thought content.

Furthermore, research suggests that people with substance-induced psychoses will later transition to a diagnosis of schizophrenia. Murrie and colleagues14 synthesized the results of longitudinal observations studies of transition from substance-induced psychosis to schizophrenia. Six studies with estimates of transition to schizophrenia among 3040 people with cannabis-induced psychosis were included. The risk of transition to schizophrenia in these individuals was 34% (95% CI 25-46%), which was the highest risk among all substances. They concluded that substance-induced psychoses are common reasons for seeking care, and these serious conditions are associated with substantial risk of transition to schizophrenia. Treatment of cannabis-induced psychoses should be considered in the same framework as that for other brief psychotic disorders (i.e., engagement, assessment, and care); this also may help decrease rates of transition to schizophrenia.

Impact of cannabis on psychotic disorders

Large and colleagues15 conducted a systematic review of the association between cannabis use and the age of onset of psychosis. They included 41 samples, finding that the age of onset of psychosis for those who used cannabis was 2.7 years younger than for non-users, corresponding to a small-to-medium effect size of 0.41. These findings are broadly consistent with a potential causal role for cannabis in the development of psychosis in some patients.

Bogaty and colleagues16 performed a meta-analysis of 14 studies of neurocognition in lifetime cannabis users and never-users in young patients with psychotic disorders (aged 15 to 45 years). They found that lifetime cannabis users performed significantly worse than never-users on several cognitive domains, including premorbid and current IQ, verbal learning and working memory, and motor inhibition. Effect sizes were small to medium for most domains (0.17-0.40), except for verbal working memory, which showed a large effect size (0.76). Interestingly, patients who use cannabis performed better on tests of conceptual set-shifting. Increasing age exacerbated the between-group differences.

Schoeler and colleagues17 conducted a systematic review and meta-analysis of the effect of continued versus discontinued cannabis use after the onset of psychosis. They identified 24 studies, including 16,565 patients with pre-existing psychosis and at least a 6 month duration of follow-up. They found that continued cannabis use was associated with a significant: increase in risk of relapse of psychosis compared with non-users (ES=0.36) and discontinued users (ES=0.28); longer hospital admissions than non-users (ES=0.36); and more severe positive, but not negative, symptoms. Krause and colleagues18 performed a meta-analysis of the efficacy, acceptability, and tolerability of antipsychotics in patients with schizophrenia and comorbid substance use. They included 8 randomized controlled trials in patients with cannabis use comorbidity. Clozapine was superior to other antipsychotics for reduction of substance use and negative symptoms in those who used cannabis. Risperidone was superior to olanzapine for reducing of drug cravings and weight gain.

Conclusions

Premorbid cannabis use is associated with a dose-dependent increased risk of developing a psychotic disorder. There is evidence in both patients with psychotic disorders and the general population that cannabis use is associated with adverse effects of psychopathology and cognition. Cannabis use and CUDs are highly prevalent throughout the clinical course of illness.

Cannabis use is associated with an earlier age of onset of psychosis and more severe impairments in neurocognition. Continued cannabis use after the onset of psychosis is associated with increased risk of illness relapse, longer hospitalizations, and more severe positive psychopathology. There is also evidence for superior efficacy of clozapine for reduction of substance use and negative symptoms in patients with schizophrenia and comorbid cannabis use. Targeted interventions for improved prevention, detection, and treatment are warranted to improve outcomes in this population.

Dr Miller is Professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the Schizophrenia Section Chief for Psychiatric Times.

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

Source: https://www.psychiatrictimes.com/view/novel-insights-cannabis-psychosis July 2020

Filed under: Brain and Behaviour,Cannabis/Marijuana :

Research suggests that smoking marijuana carries many of the same cardiovascular health hazards as smoking tobacco.

Credit…Gracia Lam

Do you have the heart to safely smoke pot? Maybe not, a growing body of medical reports suggests.

Currently, increased smoking of marijuana in public, even in cities like New York where recreational use remains illegal (though no longer prosecuted), has reinforced a popular belief that this practice is safe, even health-promoting.

“Many people think that they have a free pass to smoke marijuana,” Dr. Salomeh Keyhani, professor of medicine at the University of California, San Francisco, told me. “I even heard a suggestion on public radio that tobacco companies should switch to marijuana because then they’d be selling life instead of selling death.”

But if you already are a regular user of recreational marijuana or about to become one, it would be wise to consider medical evidence that contradicts this view, especially for people with underlying cardiovascular diseases.

Compared with tobacco, marijuana smoking causes a fivefold greater impairment of the blood’s oxygen-carrying capacity, Dr. Keyhani and colleagues reported.

In a review of medical evidence, published in January in the Journal of the American College of Cardiology, researchers described a broad range of risks to the heart and blood vessels associated with the use of marijuana.

The authors, led by Dr. Muthiah Vaduganathan, cardiologist at Brigham and Women’s Hospital in Boston, point out that “marijuana is becoming increasingly potent, and smoking marijuana carries many of the same cardiovascular health hazards as smoking tobacco.”

Edible forms of marijuana have also been implicated as a possible cause of a heart attack, especially when high doses of the active ingredient THC are consumed.

With regard to smoking marijuana, Dr. Vaduganathan explained in an interview, “The combustion products a tobacco smoker inhales have a very similar toxin profile to marijuana, so the potential lung and heart effects can be comparable. When dealing with patients, we really have to shift our approach to the use of marijuana.”

His team reported, “Although marijuana is smoked with fewer puffs, larger puff volumes and longer breath holds may yield greater delivery of inhaled elements.” In other words, when compared to tobacco smoking, exposure to chemicals damaging to the heart and lungs may be even greater from smoking marijuana.

Dr. Vaduganathan said he was especially concerned about the increasing number of heart attacks among marijuana users younger than 50. In a registry of cases created by his colleagues, in young patients suffering a first heart attack, “marijuana smoking was identified as one factor that was more common among them.” The registry revealed that, even when tobacco use was taken into account, marijuana use was associated with twice the hazard of death among those under age 50 who suffered their first heart attack.

Other medical reports have suggested possible reasons. A research team headed by Dr. Carl J. Lavie of the John Ochsner Heart and Vascular Institute in New Orleans, writing in the journal Missouri Medicine, cited case reports of inflammation and clots in the arteries and spasms of the coronary arteries in young adults who smoke marijuana.

Another damaging effect that has been linked to marijuana is disruption of the heart’s electrical system, causing abnormal heart rhythms like atrial fibrillation that can result in a stroke. In one survey of marijuana smokers, the risk of stroke was increased more than threefold.

These various findings suggest that a person need not have underlying coronary artery disease to experience cardiovascular dysfunction resulting from the use of marijuana. There are receptors for cannabinoids, the active ingredients in marijuana, on heart muscle cells and blood platelets that are involved in precipitating heart attacks.

Cannabinoids can also interfere with the beneficial effects of various cardiovascular medications, including statins, warfarin, antiarrhythmia drugs, beta-blockers and calcium-channel blockers, the Boston team noted.

The researchers found that in an analysis of 36 studies among people who suffered heart attacks, the top three triggers were use of cocaine, eating a heavy meal and smoking marijuana. And 28 of 33 systematically analyzed studies linked marijuana use to an increased risk of what are called acute coronary syndromes — a reduction of blood flow to the heart that can cause crushing chest pain, shortness of breath or a heart attack.

“In settings of an increased demand on the heart, marijuana use may be the straw on the back, the extra load that triggers a heart attack,” Dr. Vaduganathan said. He suggested that the recent decline in cardiovascular health and life expectancy among Americans may be related in part to the increased use of marijuana by young adults.

“We should be screening and testing for marijuana use, especially in young patients with symptoms of cardiovascular disease,” Dr. Vaduganathan urged.

He expressed special concern about two recent practices: the vaping of marijuana and the use of more potent forms of the drug, including synthetic marijuana products.

“Vaping delivers the chemicals in marijuana smoke more effectively, resulting in increased doses to the heart and potentially adverse effects that are more pronounced,” the cardiologist said. “Marijuana stimulates a sympathetic nervous system response — an increase in blood pressure, heart rate and demands on the heart that can be especially hazardous in people with preexisting heart disease or who are at risk of developing it.”

Dr. Vaduganathan’s team estimated that more than two million American adults who say they have used marijuana also have established cardiovascular disease, according to data from the National Health and Nutrition Examination Surveys in 2015 and 2016.

According to Dr. Keyhani, who works at the San Francisco VA Medical Center, the combination of marijuana smoking and pre-existing heart disease is especially concerning because inhaling particulate matter of any kind can harm the heart and blood vessels.

“Marijuana is a leafy green, and combustion of any plant is probably toxic to human health if the resulting products are inhaled,” she explained. “Unfortunately, the research base is inadequate because marijuana hasn’t been studied in randomized clinical trials.”

A major problem in attempts to clarify the risks of marijuana is its classification by the U.S. Drug Enforcement Administration as a Schedule I drug, making it illegal to study it rigorously in controlled clinical trials.

Scientists must then resort to the next best research method: prospective cohort studies in which large groups of people with known habits and risk factors are followed for long periods to assess their health status. “The challenge is to recruit a cohort of daily cannabis users,” Dr. Keyhani said. “It’s absolutely important to look at the health effects of cannabis now that the prevalence of daily use is increasing. The absence of evidence is not evidence of absence.”

While there are currently no official guidelines, Dr. Vaduganathan’s team urged that anyone known to be at increased risk of cardiovascular disease should be advised to minimize the use of marijuana or, better yet, quit altogether.

Source:  https://www.nytimes.com/2020/10/26/well/live/marijuana-heart-health-cardiovascular-risks.html October 2020

Filed under: Cannabis/Marijuana,Drug use-various effects,Health :

Abstract

Accidental paediatric cannabis poisonings are an incidental effect of cannabis use. The average THC content of cannabis resin and the number of consumers are rising sharply in the USA and in most European countries. The objective is to study the evolution of prevalence and severity of paediatric exposures to cannabis in France.

Method

This is a retrospective observational study of cases detected by French poison centers between January 1st 2010 and December 31st 2017 of cannabis exposure by ingestion in children aged ten or younger. The clinical severity was assessed using the Poisoning Severity Score (PSS). The criteria used for assessing the overall severity were as follows: PSS ≥ 2, admission to paediatric intensive care, coma and respiratory depression (univariate and multivariate logistic regression).

Results

A total of 965 cases of poisoning were covered. The annual average number of cases was 93 between 2010 and 2014 and 167 between 2015 and 2017. The median age was 15 months (range, 6 months–10 years) and the sex ratio was 1:1. The form of cannabis ingested was mainly resin (75%). During the period covered by the study, 26.1% of children (n = 252) presented with a PSS ≥ 2, 4.5% (n = 43) coma, 4.6% (n = 44) with respiratory depression and 11.7% (n = 113) were admitted into paediatric intensive care (out of 819 hospitalizations). No fatal cases were reported. In comparison to the 2010–2014 period, the length of hospital stays was significantly higher (p < 0.0001) and the comas were significantly deeper (lower score on the Glasgow coma scale, p < 0.005) in 2015–2017. Following adjustments made for the sex, age and weight of the children, the data show that the severity of the poisonings was significantly greater in 2015–2017 in terms of PSS score, the number of comas and monitoring in intensive care (p < 0.001).

Conclusion

The data indicates a significant increase in the number of cases of paediatric exposure to cannabis and a rise in the seriousness of poisonings between 2010 and 2017.

Source:  https://www.tandfonline.com/doi/abs/10.1080/15563650.2020.1806295 June 2020

Filed under: Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth :

A new study recently published in Nature Medicine found a stunning association between prenatal THC exposure and development of autism. Using provincial birth registries, Canadian researchers analyzed all live births that occurred in Ontario between April 2007 and March 2012 for a total of 497,821 births.

Investigators found that infants who were prenatally exposed to THC were 57% more likely to develop autism spectrum disorder (ASD) and 35% more likely to develop intellectual disabilities and learning disorders. Previous studies of this type have been difficult to interpret due to polysubstance use among expectant mothers making it difficult to tease out the effects of THC exposure alone. In this study, researchers were able to directly compare unexposed infants to those whose mothers only used marijuana during their pregnancy. Thus, any effects observed in this study can be reliably attributed to prenatal THC exposure since no other substances were used. Results persisted even adjusting for other potential risk factors for ASD such as maternal age, education, psychiatric disorders, socioeconomic status, parity, and race.

The results of this study confirm that of previous research on the harms of prenatal THC exposure. Nevertheless, marijuana is routinely recommended to pregnant women by pot docs as well as dispensary employees with no medical training at all. Given the explosion in marijuana use among pregnant women in states like FL, lawmakers must take immediate action to fund education campaigns and ban marijuana recommendations for pregnant women. How many more lives need to be ruined so that Big Pot and their political allies can line their pockets?

Source:  https://www.dfaf.org/study-finds-link-between-prenatal-thc-exposure-and-autism/ 19.08.20

Filed under: Brain and Behaviour,Cannabis/Marijuana :
Side Effects Public Media | By Alex Li
Published March 13, 2024 at 1:49 PM EDT

In 2021, fentanyl was identified in more than three-quarters of adolescent overdose
deaths, but experts say schools are slow to adapt their prevention efforts.

Alex Li was a health reporter with Side Effects Public Media based at WFYI in Indianapolis, Ind.

Li was a young and bright journalist with contagious passion and commitment to his job.

He was a beloved part of the newsroom. Li died in December 2023 and this was his last story.

Photo: Bridgesward / Pixabay

 

The majority of adults with substance use disorders start during their adolescent years. That’s why experts say prevention efforts in schools are paramount, but many schools struggle with implementation.

According to a survey by the Education Week Research Center in 2022, 67% of school health workers say that dealing with students who are vaping and using alcohol, marijuana, or opioids is “a challenge” or “a major challenge.”

The moment to address a gap in school prevention could not be more prime for action, experts say, as more young people between the ages of 10 and 19 have died of overdoses across the U.S. The driving factor behind those deaths is fentanyl, a potent synthetic opioid.

“In the era of fentanyl, with experimentation, plenty of kids die because they just don’t know that that’s a risk,” said Chelsea Shover, an epidemiologist who studies substance use at the University of California, Los Angeles.

Even a tiny amount of fentanyl can kill. In 2021, the synthetic opioid was identified in more than three-quarters of adolescent overdose deaths.

Some experts pointed out that children may purchase pain medication or prescription stimulant pills on social media, which –– unbeknown to them –– can be counterfeit and laced with fentanyl.

The U.S. Drug Enforcement Administration has seized a record 86 million fentanyl pills in 2023, which already exceeds last year’s total of 58 million pills.

Shover said, with this rapidly changing landscape, schools are slow to adapt.

“Your [school’s] alcohol and tobacco curriculum can probably stay pretty much the same. But your curriculum around opioids and overdose and street drugs needs to be updated to what’s actually happening,” she said.

Prevention sometimes takes a backseat

Schools often have more robust processes in place to react when a student is known to use substances – prevention often takes a back seat. 

The goal of these prevention efforts, experts say, should not be to tell kids to say no to drugs. Ideally, they would provide young people with facts about the health, social, and legal concerns that come with substance use and hone social skills and competencies that help kids cope with stressors.

Research suggests that social influences are central and powerful factors in both promoting and discouraging substance use among adolescents, and that many of them turn to substances to cope with anxiety or stress and some do it when they’re bored.

“When you’re talking about substance use prevention, what you’re really talking about is helping children develop the skills and competencies to withstand the pressures and to be able to prevent them from starting to use substances in the first place, or at least, knowing where to turn and those kinds of skills get built up very early,” said Ellen Quigley, vice president at the Richard M. Fairbanks Foundation. The foundation provides funding to 159 Indianapolis Schools through its Prevention Matters initiative.

Students who are not engaged in school or fail to develop or maintain relationships and those who fail academically are more likely to engage in substance use, one study found. Some of the crucial skills to teach as part of prevention efforts include conflict resolution, how to make friends, and how to deal with bullying, Quigley said.

Then, comes the messenger.

Experts say kids may be reluctant to ask for help from people who can get them in trouble like teachers and police officers. A report from the National Council for Mental Wellbeing found that only 17% of teenagers said they trust teachers or other educators. The report suggests that students have more trust in doctors, nurses and nonprofit workers.

“Drug education, it’s partly to tell students about what’s going on, and what tools are there, what risks there are, but it’s also to open a conversation for students who are struggling either themselves with substance use, or their friends are,” Shover at UCLA said.

Limited resources stand in the way

There has been substantial progress in developing and studying prevention programs for adolescent drug use, but challenges to effective implementation persist.

“While there was a lot of attention to treatment, which makes a lot of sense, there weren’t a lot of resources available for prevention,” said Quigley

Integrating prevention programs requires time and money, which some schools say they don’t usually have –– especially in lower-income communities where resources overall are limited.

One place where this is evident is Logansport School Corporation, the largest school district in Cass County, Ind. It’s a rural part of the state that is around an hour and a half north of Indianapolis, with a below-average income level. Major employers in the county are mostly manufacturing plants and meat processing facilities. Compared to most other rural communities in Indiana, the county has a large immigrant population.

Over the past few years, it has seen a steady increase in opioid use.

The school district has leaned in on peer mentorship as an approach for prevention and support to those who use substances, said Logansport School District Superintendent Michele Starkey.

“We know that those positive relationships are key to the success of students. And so that’s something that we have identified as being a huge need,” she added.

Experts say peer mentorship is a promising approach.

But the school district has had to halt other programs due to lack of funding, said Jennifer Miller, the principal of the Junior High.

“There used to be a program throughout the county that would specifically address substance abuse, vaping with the junior high level kids. And so, that doesn’t exist anymore. But there is such a need for it,” Miller said.

Tens of millions of dollars are coming to states across the country. It’s part of a major settlement with opioid manufacturers and distributors for their role in the opioid epidemic. There’s also federal and state funding available.

Logansport school district and 4C Health, a federally qualified healthcare center, got a million dollars in federal funding a few months ago.

Lisa Willis-Gidley, the Chief Revenue Officer at 4C Health, said they depend on such grants because prevention programs are not covered by insurance. Still, she says implementing effective programs can be a challenge.

“Schools don’t have a ton of time,” she said. “They’ve got to focus on their goals and their academics. And so, you have to look at can we give them these pieces of valuable material in a manner that’s not going to be totally disruptive to their academic goals and performance?”

Experts say federal and state legislation can help set standards for substance use education and ensure enough funding for schools that need it.

One of the sources in the story works for Richard M. Fairbanks Foundation, which is one of several financial supporters of WFYI. She was interviewed as we would any other source.

Side Effects Public Media is a health reporting collaboration based at WFYI in Indianapolis. We partner with NPR stations across the Midwest and surrounding areas — including KBIA and KCUR in Missouri, Iowa Public Radio, Ideastream in Ohio and WFPL in Kentucky.

Alex Li (Now deceased)
Alex covers health for Side Effects Public Media and is based at WFYI in Indianapolis, IN. He has reported on a variety of public health issues for Reuters and Xinhua. He holds a Bachelor’s degree in Government & History from Connecticut College as well as a Master’s degree in Journalism from New York University’s Arthur L. Carter Journalism Institute.
Filed under: Education,Prevention and Intervention,Youth :

Despite stereotypical images of addicts injecting heroin and then dying, new government research finds that smoking drugs such as fentanyl is now the leading cause of fatal overdoses.

In the new research, published Thursday in Morbidity and Mortality Weekly Report, scientists from the U.S. Centers for Disease Control and Prevention found the percentage of overdose deaths between January 2020 and December 2022 linked to smoking increased 73.7% — going from from 13.3% to 23.1% — while the percentage of overdose deaths linked to injection decreased 29.1% — going from from 22.7% to 16.1%.

These changes were most pronounced when fentanyl was the drug of choice: In those cases, the percentage with evidence of injection decreased 41.6%, while the percentage with evidence of smoking increased 78.9%.

CDC officials explained in their report that they decided to tackle the topic after seeing reports from California suggesting that smoking fentanyl was becoming the preferred way to use the deadly drug.

Fentanyl accounts for nearly 70% of overdose deaths in the United States, they noted.

Some early research has suggested that smoking fentanyl is somewhat less deadly than injecting it, and any reduction in injection-related overdose deaths is a positive, report author Lauren Tanz, a CDC senior scientist who studies overdoes, told the Associated Press.

However, “both injection and smoking carry a substantial overdose risk,” and it’s not clear if a shift toward smoking fentanyl will lower the number of U.S. overdose deaths, Tanz said.

Fentanyl is a powerful drug that, in powder form, is cut into heroin or other drugs. In recent years, it’s been fueling the U.S. overdose epidemic. Drug overdose deaths climbed slightly in 2022 after two big leaps during the pandemic, and provisional data for the first nine months of 2023 suggests it inched up again last year, the AP reported.

For years, fentanyl has been injected, but drug users often smoke it now. Users put the powder on tin foil or in a glass pipe, heated from below, and inhale the vapor, Alex Kral, a RTI International researcher who studies drug users in San Francisco, told the AP.

Smoked fentanyl is not as concentrated as fentanyl in a syringe, but some users see upsides to smoking, Kral explained, including the fact that people who inject drugs often deal with pus-filled abscesses on their skin and risk infections with hepatitis and other diseases.

“One person showed me his arms and said, ‘Hey, look at my arm! It looks beautiful! I can now wear T-shirts and I can get a job because I don’t have these track marks,’” Kral said.

In the new report, investigators were able to cull data from the District of Columbia and 27 states for the years 2020 to 2022. From there, they tallied how drugs were taken in about 71,000 of the more than 311,000 total U.S. overdose deaths over those three years.

By late 2022, 23% of the deaths occurred after smoking, 16% after injections, 16% after snorting and 14.5% after swallowing, the researchers reported.

Tanz said she feels the data is nationally representative because it came from states in every region of the country, and all showed increases in smoking and decreases in injecting. Smoking was the most common route in the West and Midwest, and roughly tied with injecting in the Northeast and South, the report found.

Kral noted the study has some limitations.

It can be difficult to determine the exact cause of an overdose death, especially if no witness was present, he said, and injections might be more reported more often because it is easy to spot needle marks on the body. To detect smoking as a cause of death, “they likely would need to find a pipe or foil on the scene and decide whether to write that down,” he said.

Kral added that many people who smoke fentanyl use a straw, and it’s possible investigators saw a straw and assumed it was snorted.

By Robin Foster HealthDay Reporter

SOURCE: Morbidity and Mortality Weekly Report, Feb. 16, 2024; Associated Press

More information

The National Institute on Drug Abuse has more on drug overdose deaths.

Copyright © 2024 HealthDay. All rights reserved.

Filed under: Drug use-various effects,Health :

ABSTRACT

Parental cannabis use has been associated with adverse neurodevelopmental outcomes in offspring, but how such phenotypes are transmitted is largely unknown. Using reduced representation bisulphite sequencing (RRBS), we recently demonstrated that cannabis use is associated with widespread DNA methylation changes in human and rat sperm. Discs-Large Associated Protein 2 (DLGAP2), involved in synapse organization, neuronal signaling, and strongly implicated in autism, exhibited significant hypomethylation (p < 0.05) at 17 CpG sites in human sperm. We successfully validated the differential methylation present in DLGAP2 for nine CpG sites located in intron seven (p < 0.05) using quantitative bisulphite pyrosequencing. Intron 7 DNA methylation and DLGAP2 expression in human conceptal brain tissue were inversely correlated (p < 0.01). Adult male rats exposed to delta-9-tetrahydrocannabinol (THC) showed differential DNA methylation at Dlgap2 in sperm (p < 0.03), as did the nucleus accumbens of rats whose fathers were exposed to THC prior to conception (p < 0.05). Altogether, these results warrant further investigation into the effects of preconception cannabis use in males and the potential effects on subsequent generations.

KEYWORDS: Cannabis, sperm, DNA methylation, autism, heritability

Introduction

Cannabis sativa is the most commonly used illicit psychoactive drug in the United States (U.S.) and Europe [1]. In the U.S., 11 states and Washington D.C. have legalized the recreational use of cannabis and 33 states have legalized the use of medicinal cannabis [2,3]. Since 1995, cannabis potency (defined as the concentration of the psychoactive cannabis component delta-9-tetrahydrocannabinol, or THC, in the sample [4]) has consistently risen from ~4% to as high as 32% in some states [2,5,6]. Changes in cannabis potency have been accompanied by changes in attitudes about cannabis and patterns of cannabis use. Between 2002 and 2014, the percentage of adults in the U.S. who perceived cannabis use as risky declined from 50% to 33% [6]. During this same period, the percentage of U.S. adults who believed cannabis to have no risk rose from 6% to 15% [6]. According to a 2015 Survey on Drug Use and Health, 52.5% of men in the U.S. of reproductive age (≥18) have reported cannabis use at some point in their lives, making cannabis exposure especially relevant for potential future fathers [7–11].

Given the increased prevalence of cannabis use in the U.S., studies are beginning to focus on the effects of use on the health and development of offspring. Prenatal cannabis exposure via maternal use during pregnancy is associated with decreased infant birth weight, an increased likelihood to require the neonatal intensive care unit, and the potential for an impaired fetal immune system compared to those infants who are not exposed during gestation [1,12]. In rodent studies, rat pups born to parents who were both exposed to THC during adolescence had increased heroin-seeking behaviour later in life, a phenotype that was accompanied by epigenetic changes in the nucleus accumbens [13–15]. These studies and others have begun to highlight the potential for intergenerational consequences of cannabis exposure [16]. Identifying the mechanism that underlies these changes is critical as cannabis use continues to increase across the U.S.

The environment impacts the integrity and maintenance of the epigenome such that it is now viewed as a molecular archive of past exposures [17]. While the majority of environmental epigenetic studies are focused on the impact of the inutero environment on the epigenome and health of the child, it has become apparent that the exposure history of the father must also be considered – specifically the impact of his exposures on the sperm epigenome. Studies have shown that exposure to phthalates, pesticides, nutritional deficiencies, and obesity can all induce potentially heritable changes in the sperm epigenome [18–24]. It is likely that other common and emerging exposures, including cannabis, may also contribute to disruption of sperm DNA methylation in a similar fashion, and that such changes could be transmitted to the subsequent generation.

Using reduced representation bisulphite sequencing (RRBS) our group recently demonstrated that cannabis use in humans, and THC exposure in rats, is associated with decreased sperm concentrations and widespread changes in sperm DNA methylation [25]. Of the regions identified in humans, Discs-Large Associated Protein 2 (DLGAP2) exhibited significant hypomethylation in the sperm of cannabis-exposed men compared to controls (p < 0.05). DLGAP2, a membrane-associated protein located in the post-synaptic density of neurons, plays a key role in synapse organization and neuronal signaling [26]. Dysregulation of DLGAP2 is associated with various neurological and psychiatric disorders, such as autism spectrum disorder (ASD) and schizophrenia [26–29]. In our prior screen, we identified 17 differentially methylated CpG sites within DLGAP2 in the sperm of cannabis-exposed men compared to controls. DLGAP2 was just one of 46 genes with greater than 10 CpG sites showing significantly altered DNA methylation in the sperm of cannabis users compared to controls, out of the 2,077 genes we identified as having altered DNA methylation. The first objective of this study was to validate our preliminary RRBS findings for DLGAP2 using quantitative bisulphite pyrosequencing. Our second objective was to determine the functional association between DNA methylation and gene expression of DLGAP2 to better understand how cannabis use might affect this relationship. To determine the possible intergenerational effects of paternal cannabis use, our third objective was to determine if Dlgap2 was differentially methylated in the sperm of rats exposed to THC versus controls, and if so, whether or not these changes were intergenerationally heritable.

Results

DLGAP2 is hypomethylated in sperm from cannabis users versus controls by Reduced Representation Bisulphite Sequencing (RRBS)

Our prior study [25] revealed 17 differentially methylated sites by RRBS in the sperm of cannabis users compared to controls for the DLGAP2 gene. Table S1 lists all 17 of these sites and their genomic coordinates. Figure 1a graphically demonstrates the significant hypomethylation of nine of these sites that are clustered together in the seventh intron of this gene. DLGAP2 is schematically shown in Figure 1b, including the exon-intron structure, position of CpG islands, transcription start site and the region of interest in intron 7 within the context of the gene body, with an inset showing the nucleotide sequence analysed in this study.

Validation of DLGAP2 RRBS methylation data

To confirm the methylation differences that were initially detected using RRBS, we designed a bisulphite pyrosequencing assay for the DLGAP2 intron 7 region (see Figure 1b) which captures 10 CpG sites, nine of which were identified as significantly differentially methylated using RRBS. We first validated pyrosequencing assay performance using defined mixtures of fully methylated and unmethylated human genomic DNAs. The measured levels of methylation by pyrosequencing showed good agreement between the amount of input methylation levels and the amount of methylation detected (r2 = 0.99 and p = 0.0003) (Figure 1c). These results confirmed the linearity of the assay in the ability to detect increasing amounts of DNA methylation at this region across the full range of possible methylation values, and indicate that the assay is suitable for use with biological specimens.

The DLGAP2 intron 7 region is not an imprinting control region (ICR)

DLGAP2 is paternally expressed in the testis, biallelically expressed in the brain, and has low expression elsewhere in the body [30]. Since DLGAP2 is known to be genomically imprinted in testis [30], and since the imprint control region for this gene has not yet been defined, we sought to determine if the region of interest in intron 7 is part of the DLGAP2 imprint control region (ICR). The methylation at ICRs is established during epigenome reprogramming in the primordial germ cells in embryonic development. Male and female gametes exhibit divergent methylation at ICRs, and this methylation profile is maintained through subsequent post-fertilization epigenetic reprogramming and in somatic cells throughout the life course. Therefore, we expected that if the DLGAP2 intron 7 region is an ICR, the diploid testis tissues from human conceptuses would exhibit approximately 50% methylation due to the complete methylation of one allele at this region and the complete lack of methylation at the other allele. Human conceptal testes tissues (n = 3) showed an average of 72.5% methylation at the DLGAP2 intron 7 region (Figure 1d). This finding, of higher than anticipated and variable levels of methylation, is inconsistent with ICR status.

Bisulphite pyrosequencing validates the RRBS methylation data in human sperm

We next performed quantitative bisulphite pyrosequencing on the same sperm DNA samples from cannabis users and controls as those used to generate the RRBS data to confirm the loss of methylation present at the intron 7 region of DLGAP2. All nine CpG sites that were hypomethylated in the cannabis users by RRBS were also found to be hypomethylated by bisulphite pyrosequencing, as well as an additional CpG site that was captured in the assay design (p < 0.05 for all 10 sites) (Figure 2). Following Bonferroni correction of the p value to adjust for multiple comparisons (p < 0.005), CpG sites 1,2,3,5,7,8,9, and 10 remained significant. From this pyrosequencing assay we observed methylation differences of 7–15% between the sperm of the cannabis users (n = 8) compared to controls (n = 7). Correlation of the RRBS and pyrosequencing data for each individual CpG site showed significant agreement at all sites analysed (p < 0.02 for all sites; Figure S1). All CpG sites showed a significant loss of methylation in accordance with the direction of change observed by RRBS for these same CpG sites.

Methylation of DLGAP2 intron 7 is inversely correlated with DLGAP2 expression

Given that we observed significant loss of intron 7 DLGAP2 DNA methylation in sperm of cannabis users relative to non-users, we next examined the relationship between DNA methylation and gene expression in the brain, where this gene’s function is critical. We used 28 conceptal brain tissues to examine the relationship between DNA methylation and mRNA expression. Expression levels were normalized to the lowest expressing sample, and the relationship between DNA methylation and mRNA expression was calculated with a Pearson correlation. We found that as methylation increased in this region, mRNA expression decreased significantly (p < 0.05) (Figure 3a). Knowing that there are sex differences in autism spectrum disorder (ASD), and that dysregulation of DLGAP2 is associated with ASD [26], we sought to determine if there were any sex differences in the methylation-expression relationship in these tissues. To investigate this, we ran the correlation for males (n = 15) and females (n = 13) independently. The inverse relationship between methylation and expression was evident for both males and females, but this relationship was significant only in females (p = 0.006) (Figure 3b, c).

Intergenerational inheritance of altered Dlgap2 DNA methylation

We next sought to investigate Dlgap2 using data obtained from our prior study [25] to determine if there was any differential methylation of Dlgap2 in THC versus control rats that was not initially identified using the imposed thresholds of that study. We were particularly interested in the potential for intergenerational transmission and to determine if route of THC exposure affected DNA methylation at this gene. The pilot study rats [25] were given THC via oral gavage (to mimic oral ingestion of drug) while subsequent studies dosed rats via intraperitoneal injection (to mimic inhalation of drug). From the rats administered THC via oral gavage versus controls, we identified a region of Dlgap2 that showed differential methylation by the RRBS analysis that contains eight CpG sites. This region is in the first intron of Dlgap2, in a CpG island that spans the first exon of this gene as well (schematic of the gene structure and sequence of this region shown in Figure 4a). We validated the rat Dlgap2 pyrosequencing assay using commercially available rat DNA of defined methylation status. The results showed good agreement between the input methylation and the amount of methylation detected by pyrosequencing (r2 = 0.92, p = 0.01) (Figure 4b).

We were able to demonstrate intergenerational inheritance of an altered DNA methylation pattern in Dlgap2. Comparing the average methylation for exposed and unexposed sperm for each CpG site revealed that sites 2,3,4 and 6 of the eight CpG sites analysed were significantly hypomethylated in the sperm of rats exposed via injection to 4mg/kg THC compared to controls (p = 0.03 to p = 0.005) (Figure 4c). CpG site 6 remained significant after Bonferroni correction (p < 0.006). The same region of Dlgap2 was then analysed in the hippocampus and nucleus accumbens of rats whose fathers were exposed to control or 4mg/kg THC. While CpG site 7 was significantly hypomethylated (p < 0.05) in the hippocampus of the offspring (Figure 5a), this site was not identified as differentially methylated in the sperm of THC exposed rats, and therefore we could not conclude that this change was transmitted as the result of changes present in the exposed sperm. In the nucleus accumbens, however, significant hypomethylation (p = 0.02) at CpG site 2 was detected in the offspring (Figure 5b), one of the same sites identified in the sperm of THC exposed rats. We also found that there was an inverse relationship between DNA methylation and expression of Dlgap2 in the nucleus accumbens, though not statistically significant likely due to the small sample size available in this study (n = 6 exposed, n = 8 unexposed; Figure S2).

Discussion

In this study, we examined the effects of regular male cannabis use on human sperm DNA methylation, at DLGAP2. Our RRBS study initially identified 17 CpG sites in DLGAP2 that were differentially methylated in the sperm of cannabis users compared to controls. Of the sites that were initially identified, nine of them all reside together in the seventh intron of this gene, though not in a defined CpG island. To first confirm the RRBS data, we performed quantitative bisulphite pyrosequencing for the nine clustered CpG sites. We were able to capture an additional CpG site with careful assay design for a total of ten CpG sites analysed via bisulphite pyrosequencing. We successfully validated the RRBS findings, confirming that there was significant hypomethylation among these ten sites with cannabis use. We confirmed a significant inverse correlation between methylation and expression at this region in human conceptal brain tissues.

To begin to determine whether or not the effects of cannabis on sperm are heritable, we analysed sperm from THC exposed and control male rats, as well as the hippocampus and nucleus accumbens from offspring of THC exposed and control males for changes in DNA methylation at Dlgap2. Rats exposed to THC were given a dose (4mg/kg THC for 28 days) that is pharmacodynamically equivalent to daily cannabis use to resemble frequent use in humans. We identified significant hypomethylation at Dlgap2 in the sperm of exposed rats as compared to controls. This hypomethylated state was also detected in the nucleus accumbens of rats born to THC exposed fathers compared to controls, supporting the potential for intergenerational inheritance of an altered sperm DNA methylation pattern. While the changes in the degree of methylation are small in the rats (0.5–0.7%), we previously reported that fractional changes in methylation can significantly influence the degree to which the gene’s expression is altered [31].

DLGAP2 is a member of the DLGAP family of scaffolding proteins located in the post-synaptic density (PSD) of neurons. The PSD is a protein-dense web that lies under the postsynaptic membrane of neurons and facilitates excitatory glutamatergic signaling in the central nervous system [26,32]. DLGAP2 functions to transmit neuronal signals across synaptic junctions and helps control downstream signaling events [26,32]. Due to its important role in PSD signaling, even small changes in the expression of DLGAP2 can have severe consequences [26,32]. Of particular relevance, DLGAP2 has been linked to schizophrenia and importantly, has been identified as an autism candidate gene [27,28,33,34]. Differential methylation of DLGAP2 is reported in the brain of individuals with autism, and has been linked to post-traumatic stress disorder in rats [27,35]. Knockout of Dlgap2 in mice results in abnormal social behaviour, increased aggressive behaviour, and learning deficits [36].

Studies are increasingly showing associations between cannabis use and various neuropsychiatric and behavioural disorders including anxiety, depression, cognitive deficits, autism, psychosis, and addiction [2,6,7,9,14,37–39]. Research looking into the effects of THC exposure found that rat pups born to parents who were exposed to THC during adolescence showed increased effort to self-administer heroin compared to those born to unexposed parents [13]. This increase in addictive behaviour was driven by THC-induced changes in DNA methylation, occurring in the striatum, including the nucleus accumbens [14,15]. One of the genes whose methylation was altered by parental THC exposure was Dlgap2 [15]. Recently, a group from Australia analysed datasets from two independent cohorts to examine the relationship between cannabis legalization in the U.S. and ASD incidence. They determined there was a strikingly significant positive association between cannabis legalization and increased ASD incidence. Further, the study authors predicted that there will be a 60% increase in excess ASD cases in states with legal cannabis by 2030, and deemed ASD the most common form of cannabis-associated clinical teratology [40].

It is estimated that the ratio of boys with ASD to girls with ASD is 4:1 which led us to stratify our analysis looking at the relationship between DNA methylation and gene expression by sex [41,42]. The results of our methylation-expression analyses demonstrated a significant association in females but not males. While we don’t know the ASD status of these samples, there are several reasons why this may be the case. First, there are certain genes that confer a stronger ASD phenotype in girls compared to boys [41,42]. Thus, while we see the trend in both sexes, it is possible that dysregulation of this gene may manifest phenotypically more in girls. Alternatively, it may be that the regulatory relationship between methylation and expression is retained in females while altered methylation further exacerbates an already fragile relationship in males. Overall, this data confirms that the region of DNA methylation within DLGAP2 that was differentially methylated in the sperm of cannabis users compared to controls is functionally important in the brain.

DLGAP2 is an imprinted gene that exhibits paternal expression in the testis, biallelic expression in the brain, and low expression elsewhere in the body [30]. Because the methylation established at imprinted genes resists post-fertilization epigenetic reprogramming [43–45], this supports the possibility that changes in methylation at DLGAP2 in sperm could be transmitted to the next generation. However, given that the region in intron 7 is not an ICR, it is unlikely that this would be a potential mechanism for intergenerational inheritance of an altered methylation pattern at this region. However, it has recently been discovered that a subset of genes termed ‘escapees’ are able to escape primordial germ cell (PGC) and post-fertilization reprogramming events [46,47], providing a mechanism for epigenetic changes incurred by sperm to be passed on to the subsequent generation.

Processes in the PSD are sensitive to endocannabinoids [26,48–51], which suggests that these processes are potentially sensitive to exogenous cannabinoids, such as THC and cannabis. This is especially important as cannabis legalization and use are increasing dramatically across the U.S. It is estimated that 22% of American adults currently use cannabis, of which 63% are regular users (≥1–2 times per month) [7–10]. Among regular users 55% are males and over half of all men over 18 have reported cannabis use in their lifetime [7–10]. Importantly, this age range includes individuals of reproductive age. Since almost half of all pregnancies in the U.S. are unplanned, there is concern that many pregnancies may occur during a time when one, or both, parents are using or are exposed to cannabis [52].

Our results provide novel findings about the effects of paternal cannabis use on the methylation status of an ASD candidate gene, a disorder whose rates continue to climb, but whose precise aetiologies remain unknown. Studies are beginning to show that there is a potential for paternal intergenerational inheritance. In particular, epigenetic changes in umbilical cord blood of babies born to obese fathers were also found in the sperm of obese men. This study is the first to demonstrate that there are changes present in the sperm epigenome of cannabis users at a gene involved in ASD.

The results of this study have several limitations. The sample size was small, which might limit generalization of the study findings. However, even though our sample size was small, we were able to identify common pathways that were differentially methylated in both human and rat sperm, highlighting the potential specificity of these effects [25]. We did not account for a wide variety of potential confounders such as various lifestyle habits, sleep, diet/nutrition, exercise, etc, given that their influence on the sperm DNA methylome is largely unknown. Larger studies are required to confirm these findings. In the conceptal tissues we were only able to analyse whole brain, rather than the areas where DLGAP2 is most highly expressed such as the hippocampus and the striatum, which could have diluted the strength of the results.

Strengths of the study included that we used a highly quantitative method to confirm the methylation status that was measured by RRBS. This study was the first demonstration of the association between cannabis use and substantial hypomethylation of DLGAP2 in human sperm. Additionally, we are able to confirm a functional relationship between methylation and expression in a relevant target tissue, and have shown that the relationship between methylation and expression is weakened in males, which could bear relevance to the sexual dimorphism in the prevalence of autism. This is the first demonstration of potential heritability of altered methylation resulting from preconceptional paternal THC exposure. Given the increasing legalization and use of cannabis in the U.S., our results underscore a need for larger studies to determine the potential for heritability of DLGAP2 methylation changes in the human F1 generation and beyond. It will also be important to examine how cannabis-associated methylation changes relate to neurobehavioral phenotypes

Source:   Epigenetics. 2020; 15(1-2): 161–173.

Published online 2019 Aug 26. doi: 10.1080/15592294.2019.1656158

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth,Effects of Drugs (Papers) :

To Whom it may concern

On behalf of Drug Free Australia and our coalition of drug prevention researchers, we wish to commend to you, research that could well be a game-changer in informing and preventing a large proportion of Australia’s substance use issues.

The research is in various stages of development and a synopsis of current and emerging research, being done by Dr Stuart Reece and Professor Gary Hulse should be of genuine interest for all Australian Health Professionals. However, it appears that, to date, too many of the world’s researchers have placed this important research in the ‘too hard’ basket, similar to the way the NHS in the United Kingdom did with research into Pandemics.

At present the COVID-19 pandemic and how it is being addressed, should be a ‘wakeup call’ to Australian health authorities that prevention is the single most important goal. A ‘Harm Minimisation’ only approach, fails to achieve best-practice primary prevention outcomes. The passive discounting of the primary pillar of the National Drug Strategy – Demand Reduction over the last 30 years (and particularly the last 10) has seen a very large increase in illegal drug use in this nation.

The only exception to this has been seen in the correct and full use of both demand and supply reduction on the drug Tobacco. There has been little or no use of harm reduction mechanisms and a relentless and unified approach to abstinent/cessation modelling and it has worked spectacularly well, seeing Australia with, arguably, the lowest daily tobacco use in the world.

The research, that we now summarise, should not be placed in Australia’s ‘too hard’ basket. Rather, it warrants recognition by all Australian Health authorities for the world break-through that it is. Such evidence-based data offers timely insights that should promote and resource primary prevention and demand reduction.

Synopsis of the research:
1. Canadian Cannabis Consumption and Patterns of Congenital Anomalies: An Ecological Geospatial Analysis Albert Stuart Reece, MBBS(Hons), FRCS(Ed), FRCS(Glas), FRACGP, MD(UNSW), and Gary Kenneth Hulse, BBSc(Hons), MBSc, PhD
https://journals.lww.com/journaladdictionmedicine/Abstract/publishahead/Canadian_Cannabis_Consumption_and_Patterns_of.99248.aspx

Status
Mapping showed cannabis use was more common in the northern Territories of Canada in the Second National Survey of Cannabis Use 2018. Total congenital anomalies, all cardiovascular defects, orofacial clefts, Downs syndrome and gastroschisis were all found to be more common in these same regions and rose as a function of cannabis exposure.

When Canada was dichotomized into high and low cannabis use zones by Provinces v Territories the Territories had a higher rate of total congenital anomalies 450.026 v 390.413 (O.R.=1.16 95%C.I. 1.08-1.25, P=0.000058; attributable fraction in exposed 13.25%, 95%C.I. 7.04–19.04%). In geospatial analysis in a spreml spatial error model cannabis was significant both alone as a main effect (P<2.0×10-16) and in all its first and second order interactions with both tobacco and opioids from P<2.0×10-16.

Conclusion:

These results show that the northern Territories of Canada share a higher rate of cannabis use together with elevated rates of total congenital anomalies, all cardiovascular defects, Down’s syndrome and gastroschisis. This is the second report of a significant association between cannabis use and both total defects and all cardiovascular anomalies and the fourth published report of a link with Downs syndrome and thereby direct major genotoxicity.

The correlative relationships described in this paper are confounded by many features of social disadvantage in Canada’s northern territories. However, in the context of a similar broad spectrum of defects described both in animals and in epidemiological reports from Hawaii, Colorado, USA and Australia they are cause for particular concern and indicate further research.

139 References – click on this link to access.
https://journals.lww.com/journaladdictionmedicine/Abstract/publishahead/Canadian_Cannabis_Consumption_and_Patterns_of.99248.aspx

2. Cannabis Consumption Patterns Parallel the East-West Gradient in Canadian Neural Tube Defect Incidence – An Ecological Study
https://www.researchgate.net/publication/337911618_Cannabis_Consumption_Patterns_Explain_the_East-West_Gradient_in_Canadian_Neural_Tube_Defect_Incidence_An_Ecological_Study

Status:
Whilst a known link between prenatal cannabis exposure (PCE) and anencephaly exists, the relationship of PCE with neural tube defects (NTD’s) generally has not been defined. Published data from Canada Health and Statistics Canada was used to assess this relationship. Both cannabis use and NTDs were shown to follow an east-west and north-south gradient. Last year cannabis consumption was significantly associated (P<0.0001; Cannabis use: time interaction P<0.0001). These results were confirmed when estimates of termination for anomaly were used. Canada Health population data allowed the calculation of an NTD O.R.=1.27 (95%C.I. 1.19-1.37; P<10-11) for high risk provinces v. the remainder with an attributable fraction in exposed populations of 16.52% (95%C.I. 12.22-20.62). Data show a robust positive statistical association between cannabis consumption as both a qualitative and quantitative variable and NTDs on a background of declining NTD incidence. In the context of multiple mechanistic pathways these strong statistical findings implicate causal mechanisms.

82 References – click on this link to access.
https://www.researchgate.net/publication/337911618_Cannabis_Consumption_Patterns_Explain_the_East-West_Gradient_in_Canadian_Neural_Tube_Defect_Incidence_An_Ecological_Study

3. Cannabis exposure as an interactive cardiovascular risk factor and accelerant of organismal ageing: a longitudinal study. Response to Lane
https://bmjopen.bmj.com/content/6/11/e011891.responses

Status:
We wish to thank Dr Lane for his interest in our study. We are pleased to see statistical input to the issues of cannabis medicine as we feel that sophisticated statistical methodologies have much to offer this field.

Most of the concerns raised are addressed in our very detailed report. As described our research question was whether, in our sizeable body of evidence (N=13,657 RAPWA studies), we could find evidence for the now well-described cannabis vasculopathy and what such implications might be. As this was the first study of its type to apply formal quantitative measures of vascular stiffness to these questions it was not clear at study outset if there would be any effect, much less an estimate of effect size. In the absence of this information power calculations would be mere guesswork. Nor indeed are they mandatory in an exploratory study of this type. Similarly the primary focus of our work was on whether cannabis exposure was an absolute cardiovascular risk factor in its own right, and how it compared to established risk factors. Hence Table 2 contains our main results. The role of Table 1 is to illustrate the bivariate (uncorrected) comparisons which can be made, show the various groups involved, and compare the matching of the groups. It is not intended to be a springboard for effect-size-power calculations which are of merely esoteric interest.
Calculations detailing the observed effect size are clearly described in our text being 11.84% and 8.35% age advance in males and females respectively.

Mixed-effects models are the canonical way to investigate longitudinal data given a usual random error structure 1. We agree with Lane that unusual error structures can affect significance conclusions. Diagnostic tests run on our models confirm that the residuals had the usual spheroidal error structure so that the application of mixed-effects models in the classical way is quite satisfactory. Another way to investigate this issue is that of incremental model building comparing models with and without cannabis exposure terms. If one considers regression equations from our data with cannabis use treated either as a categorical (RA/CA ~ Days_Post-Cannabis * BMI + * Cannabis_Category) or a continuous (RA/(CA*BMI) ~ Cigs*SP + * Cannabis_Use +Chol+DP+HDL+HR+CRH) variable one notes firstly that terms including cannabis use remain significant in final models (after model reduction) and secondly that models which include cannabis exposure are significantly better than ones without (Categorical: AIC = 1088.56 v. 1090.22, Log.Ratio = 19.62, P = 0.0204; Continuous: AIC = 412.33 v. 419.73, Log.Ratio = 9.37, P = 0.0022). Unfortunately formatting rules for BMJ Rapid Responses do not allow us to include a detailed table of regression results in each model in the present reply. We also note that AIC’s are little used in our report, and simply indicate the direction of the ANOVA results comparing models linear, quadratic and cubic in chronological age. They also appear routinely in the display of mixed-effects model results. Their use in such contexts is methodologically unremarkable. Control groups are also spelled out in fine detail in Table 1, in all our Figures and in the text.

We are aware that various algorithms for vascular age have been reported in the literature. The list proposed by Lane is correct but non-exhaustive. Such algorithms are generally derived from known cardiovascular risk factors. As clearly stated in our report the algorithm for vascular age we employed is derived from the proprietary software used. As such its details have not been publicized and indeed are commercially protected information.

We have however been assured by AtCor on many occasions that it includes measures of chronological age, sex, arterial stiffness and height (which is important as it dictates distance and thus speed parameters for the reflected and augmented central arterial pressure waves) and is very well validated and tested. AtCor recently advised that their algorithm is based on a very large series of studies done with arterial stiffness published in 2005 2. As such it has distinct advantages over algorithms which do not include indices of arterial stiffness. The AtCor website includes a very interesting, informative and educative animated loop which clearly illustrates the complex relationship between chronological and vascular age as a function of arterial stiffness and vascular tone 3

We are keen to see advanced statistical methods applied to such questions. We are becoming interested in geospatial and spacetime analyses and its application to the important questions of cannabis epidemiology 4. We find the very breadth of the organ systems impacted by cannabis to be quite remarkable with effects on the brain, cardiovasculature, liver, lungs, testes, ovaries, gastrointestinal, endocrine, reproductive and immune systems being well described and constituting most of the body’s major systems 5 6. Testicular and several pediatric cancers have also been described as being cannabis-associated 5. Such a multisystem generality of toxicity suggests to us that some basic cellular functions may be deleteriously affected – as implied by its well described mitochondriopathy 7, its heavy epigenetic footprint 8, accelerated aging as described in our present report 9 or some multi-way interaction between these and other processes. Given that the cannabis industry is presently entering a major commercialization growth phase, and given the multigenerational implications of mitochondriopathy-epigenotoxicity (by direct: substrate supply including ATP, NAD+ and acetate; and indirect: RNA transfer and malate-aspartate and glycerol-3-phosphate shuttle; pathways 10) further study and elucidation of these points is becoming an increasingly imperative international research priority.

Apropos of the recent Covid-19 pandemic emergency it is also worth noting that since cannabis is immunosuppressive, is known to be damaging to lungs and airways and often carries chemical, microbial and fungal contaminants cannabis use and cannabis vaping is also likely to have a deleterious effect on the coronavirus epidemic. Such data implies an untoward convergence of two public health epidemics. Appropriate controls on cannabis use imply improved public health management of SARS-CoV-2.

10 References – click on this link to access. https://bmjopen.bmj.com/content/6/11/e011891.responses

4. Cannabis Teratology Explains Current Patterns of Coloradan Congenital Defects: The Contribution of Increased Cannabinoid Exposure to Rising Teratological Trends.
https://www.researchgate.net/publication/334368364_Cannabis_Teratology_Explains_Current_Patterns_of_Coloradan_Congenital_Defects_The_Contribution_of_Increased_Cannabinoid_Exposure_to_Rising_Teratological_Trends/link/5d2d4d39a6fdcc2462e3097c/download

Status
Rising Δ9-tetrahydrocannabinol concentrations in modern cannabis invites investigation of the teratological implications of prenatal cannabis exposure.

Data from Colorado Responds to Children with Special Needs (CRCSN), National Survey of Drug Use and Health, and Drug Enforcement Agency was analyzed. Seven, 40, and 2 defects were rising, flat, and falling, respectively, and 10/12 summary indices rose. Atrial septal defect, spina bifida, microcephalus, Down’s syndrome, ventricular septal defect, and patent ductus arteriosus rose, and along with central nervous system, cardiovascular, genitourinary, respiratory, chromosomal, and musculoskeletal defects rose 5 to 37 times faster than the birth rate (3.3%) to generate an excess of 11 753 (22%) major anomalies. Cannabis was the only drug whose use grew from 2000 to 2014 while pain relievers, cocaine, alcohol, and tobacco did not. The correlation of cannabis use with major defects in 2014 (2019 dataset) was R = .77, P = .0011. Multiple cannabinoids were linked with summary measures of congenital anomalies and were robust to multivariate adjustment.

66 References – click on this link to access
https://www.researchgate.net/publication/334368364_Cannabis_Teratology_Explains_Current_Patterns_of_Coloradan_Congenital_Defects_The_Contribution_of_Increased_Cannabinoid_Exposure_to_Rising_Teratological_Trends/link/5d2d4d39a6fdcc2462e3097c/download

5. Impacts of cannabinoid epigenetics on human development: reflections on Murphy et. al. ‘cannabinoid exposure and altered DNA methylation in rat and human sperm’ epigenetics 2018; 13: 1208-1221.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773386/pdf/kepi-14-11-1633868.pdf
Status

ABSTRACT Recent data from the Kollins lab (‘Cannabinoid exposure and altered DNA methylation in rat and human sperm’ Epigenetics 2018; 13: 1208–1221) indicated epigenetic effects of cannabis use on sperm in man parallel those in rats and showed substantial shifts in both hypo- and hyper-DNA methylation with the latter predominating. This provides one likely mechanism for the transgenerational transmission of epigenomic instability with sperm as the vector. It therefore contributes important pathophysiological insights into the probable mechanisms underlying the epidemiology of prenatal cannabis exposure potentially explaining diverse features of cannabis-related teratology including effects on the neuraxis, cardiovasculature, immune stimulation, secondary genomic instability and carcinogenesis related to both adult and pediatric cancers. The potentially inheritable and therefore multigenerational nature of these defects needs to be carefully considered in the light of recent teratological and neurobehavioural trends in diverse jurisdictions such as the USA nationally, Hawaii, Colorado, Canada, France and Australia, particularly relating to mental retardation, age-related morbidity and oncogenesis including inheritable cancerogenesis.

Increasing demonstrations that the epigenome can respond directly and in real time and retain memories of environmental exposures of many kinds implies that the genome-epigenome is much more sensitive to environmental toxicants than has been generally realized. Issues of long-term multigenerational inheritance amplify these concerns. Further research particularly on the epigenomic toxicology of many cannabinoids is also required. 

206 References – click on this link to access

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773386/pdf/kepi-14-11-1633868.pdf

6. Canadian Cannabis Consumption and Patterns of Congenital Anomalies: An Ecological Geospatial Analysis.
https://www.ncbi.nlm.nih.gov/pubmed/32187114

Status:
These results show that the northern Territories of Canada share a higher rate of cannabis use together with elevated rates of total congenital anomalies, all cardiovascular defects, Down’s syndrome and gastroschisis. This is the second report of a significant association between cannabis use and both total defects and all cardiovascular anomalies and the fourth published report of a link with Downs syndrome and thereby direct major genotoxicity. The correlative relationships described in this paper are confounded by many features of social disadvantage in Canada’s northern territories. However, in the context of a similar broad spectrum of defects described both in animals and in epidemiological reports from Hawaii, Colorado, USA and Australia they are cause for particular concern and indicate
further.

139 references – click on this link to access https://www.ncbi.nlm.nih.gov/pubmed/32187114

7. The Potential Association Between Prenatal Cannabis use and Congenital Anomalies
https://journals.lww.com/journaladdictionmedicine/Citation/9000/The_Potential_Association_Between_Prenatal.99243.aspx

Status:
Rates of prenatal cannabis use are likely to rise with legalization, increasing social tolerability, and promotion in social media. Cannabis consumption does not appear to be a benign activity, and there may be significant risk factors to the developing fetus when used in pregnancy. Even as epidemiological data continue to emerge, The American College of Obstetricians and Gynecologists and The Society of Obstetricians and Gynecologists of Canada recommend that women avoid the use of cannabis during pregnancy.14 Whether we will definitively establish the risk of prenatal cannabis use on congenital anomalies using epidemiological approaches remains unclear; however, combing data from ecological and patient-level approaches will be crucial. Patient engagement and increasing awareness of the health implications of cannabis are critical first steps to highlight the potential risks of cannabis use in pregnancy.

14. References – click on this link to access
https://journals.lww.com/journaladdictionmedicine/Citation/9000/The_Potential_Association_Between_Prenatal.99243.aspx

8. America Addresses Two Epidemics – Cannabis and Coronavirus and their Interactions: An Ecological Geospatial Study
Status: Embargoed until publication.

Question: Since cannabis is immunosuppressive and is frequently variously contaminated, is its use associated epidemiologically with coronavirus infection rates?

Findings: Geospatial analytical techniques were used to combine coronavirus incidence, drug and cannabinoid use, population, ethnicity, international flight and income data. Cannabis use and daily cannabis use were associated with coronavirus incidence on both bivariate regression and after multivariable spatial regression with high levels of statistical significance. Cannabis use quintiles and cannabis legal status were also highly significant.

Meaning: Significant geospatial statistical associations were shown between cannabis use and coronavirus infection rates consistent with mechanistic reports and environmental exposure concerns.

Extracts from Abstract:

Results. Significant associations of daily cannabis use quintile with CVIR were identified with the highest quintile having a prevalence ratio 5.11 (95%C.I. 4.90-5.33), an attributable fraction in the exposed (AFE) 80.45% (79.61-81.25%) and an attributable fraction in the population of 77.80% (76.88-78.68%) with Chi-squared-for-trend (14,782, df=4) significant at P<10-500. Similarly when cannabis legalization was considered decriminalization was associated with an elevated CVIR prevalence ratio 4.51 (95%C.I. 4.45-4.58), AFE 77.84% (77.50-78.17%) and Chi-squared-for-trend (56,679, df=2) significant at P<10-500. Monthly and daily use were linked with CVIR in bivariate geospatial regression models (P=0.0027, P=0.0059). In multivariable additive models number of flight origins and population density were significant. In interactive geospatial models adjusted for international travel, ethnicity, income, population, population density and drug use, terms including last month cannabis were significant from P=7.3×10-15, daily cannabis use from P=7.3×10-11 and last month cannabis was independently associated (P=0.0365).

Conclusions and Relevance. Data indicate CVIR demonstrates significant trends across cannabis use intensity quintiles and with relaxed cannabis legislation. Recent cannabis use is independently predictive of CVIR in both bivariate and multivariable adjusted models and intensity of use is significant in several interactions. Cannabis thus joins tobacco as a SARS2-CoV-2 risk factor.

Summary and Conclusions

The above research clearly shows the links with substance use and Mental illness, Autism, Congenital anomalies and Paediatric cancer including testicular cancer with marijuana use and abuse. Drug Free Australia respectfully and urgently requests a Position Statement and proposed actions from your Department regarding this research and how it can be further promoted and supported within Australia. We look forward to your timely response.

You can find a list of list of Ngo’s and Medical Professional who written support for Drug Free Australia’s Response to the commercialization of Cannabis/Marijuana/CBD in Australia

https://drugfree.org.au/images/pdf-files/homepagepdf/DRReeceSupport2020_updated6May2020.pdf.

Yours sincerely
Major Brian Watters AO B.A.
President
Drug Free Australia
PO Box 379
Seaford, SA 516

 

Filed under: Australia,Cannabis/Marijuana,Drug use-various effects,Drug use-various effects on foetus, babies, children and youth,Health :

Highlights

  • Population-based longitudinal cohort study over 30 years spanning age 19/20 to 49/50
  • Cannabis use in adolescence predicted the occurrence of depression and suicidality in adulthood
  • Association between adolescent cannabis use and adult depression/suicidality hold when adjusted for various covariates, including time-varying pattern of substance abuse in adulthood
  • Younger age at first cannabis use and more frequent use in adolescence related to an particularly increased risk of adult depression

Abstract

  • Objective

    To examine the association between cannabis use in adolescence and the occurrence of depression, suicidality and anxiety disorders during adulthood.

  • Methods

    A stratified population-based cohort of young adults (n = 591) from Zurich, Switzerland, was retrospectively assessed at age 19/20 for cannabis use in adolescence. The occurrence of depression, suicidality and anxiety disorders was repeatedly assessed via semi-structured clinical interviews at the ages of 20/21, 22/23, 27/28, 29/30, 34/35, 40/41, and 49/50. Associations were controlled for various covariates, including socio-economic deprivation in adolescence as well as repeated time-varying measures of substance abuse during adulthood.

  • Results

    About a quarter (24%) reported cannabis use during adolescence; 11% started at age 15/16 or younger and 13% between the ages of 16/17 and 19/20. In the adjusted multivariable model, cannabis use during adolescence was associated with adult depression (aOR = 1.70, 95%-CI = 1.24–2.32) and suicidality (aOR = 1.65, 95%-CI = 1.11–2.47), but not anxiety disorders (aOR = 1.10, 95%-CI = 0.82–1.48). First use at age 15/16 and younger (as against first use between age 16/17 and 19/20 and no use) and frequent use in adolescence (as against less frequent use and no use) were associated with a higher risk of depression in adult life.

  • Conclusions

    In this longitudinal cohort study over 30-years, cannabis use during adolescence was associated with depression and suicidality in adult life. Young age at first use and high frequency of use in adolescence may particularly increase the risk of depression in adulthood. All associations were independent of cannabis abuse and other substance abuse during adulthood.

Introduction

An extensive body of evidence suggests that cannabis use in adolescence increases the risk of adult psychotic disorders (Arseneault et al., 2002, Moore et al., 2007, Rossler et al., 2012); based on Mendelian randomization studies it appears that this association may at least partly be causal (Gage et al., 2017, Vaucher et al., 2018). However, it is less clear whether adolescent cannabis use also predicts depression and other affective disorders (Moore et al., 2007). For instance, a recent 35-year longitudinal cohort study of male conscripts found a weak association between cannabis use and an increased risk for depression, but this association disappeared after adjustment for covariates (Manrique-Garcia et al., 2012).

Another prospective population-based study over 3 years including both male and female adults likewise found that cannabis use at baseline weakly increased the risk of depression and anxiety, but once again these associations disappeared after controlling for covariates (comprising alcohol and drug use, education level, and family climate) (Danielsson et al., 2016). In contrast, a longitudinal cohort study of 14-15 year-old students followed over seven years reported a remarkably strong association between early cannabis use and later depression and anxiety that persisted after adjustment for baseline covariates (Patton et al., 2002). Finally, a recent meta-analysis of longitudinal studies found that adolescent cannabis use predicts the development of depression (OR = 1.4), suicidal ideation (OR = 1.5) and suicide attempts (OR = 3.5), but not anxiety (OR = 1.2), in young adulthood (Gobbi et al., 2019).

The aim of the present work was to re-address the association between adolescent cannabis use and later mood and anxiety disorders. We extended previous research by focusing separately on mood disorders, anxiety disorders and suicidality. Moreover, we did not only control for baseline covariates, such as family climate and socio-economic background, but also for concomitant abuse of both alcohol and illicit drugs (including both cannabis and other substances) across the participants’ adult lives. Finally, with a total observation period of 30 years, the present longitudinal study is much longer than most research conducted thus far.

Section snippets

Participants and sampling procedure

The Zurich Study comprised a cohort of 4547 subjects (m = 2201; f = 2346) representative of the canton of Zurich in Switzerland, who were screened in 1978 with the Symptom Checklist 90-Revised (SCL-90-R) (Derogatis, 1977) when males were 19 and females 20 years old. Male and female participants were sampled with different approaches. In Switzerland, every man of Swiss nationality must undertake a military screening test at the age of 19. With the consent of the military authorities, but…

Results

Comprehensive dropout analyses of this cohort have been presented elsewhere (Eich et al., 2003, Hengartner et al., 2016). In short, dropouts appeared to be either extremely low or extremely high scorers on the SCL GSI, but except for a weak gender bias (men were more likely to drop out) there were no baseline characteristics that predicted early study termination. The frequencies of adolescent cannabis use and baseline socio-demographic characteristics are shown in Table 1. In total 143 of 586…

Discussion

In this 30-year longitudinal cohort-study we examined the associations between cannabis use in adolescence (i.e. before the age of 19/20 years) and the development of depressive disorders, severe suicidality and anxiety disorder during adulthood (i.e. between the ages of 20/21 and 49/50). Our results show that cannabis use in adolescence, independently of substance abuse in adulthood, is significantly related to the occurrence of depressive disorders and severe suicidality, but not to anxiety…

Funding

The Zurich Cohort Study was supported by the Swiss National Science Foundation (Grant number 32-50881.97). The donator/sponsor had no further role in the experimental design, the collection, analysis, and interpretation of data, the writing of this report, or the decision to submit this paper for publication…

Author contributions

MPH drafted the manuscript and conducted all statistical analyses; JA and WR contributed to design and conduct of the study, interpretation of the data and critical revision of the manuscript; VAG contributed to interpretation of the data and critical revision. All authors approved the final version of this manuscript…

Source: https://www.sciencedirect.com/science/article/abs/pii/S0165032719320919 May 2020

Filed under: Brain and Behaviour,Cannabis/Marijuana,Drug use-various effects on foetus, babies, children and youth :

The sale and use of illegal drugs are among the most serious problems facing the UK, indeed, the entire world, right now. This issue is particularly prevalent within Britain’s night-time economy, where even the most stringently law-abiding and responsibly run premises are not guaranteed to be completely free from the presence of drugs and/or drug dealers.

As a security operative, especially a door supervisor, you are in a unique position to spot potential drug deals and put a stop to them. This is of benefit to both the venue as well as its patrons. Overall, it also helps to keep the public safe.

In this feature, we’ll show you to spot a probable drug deal, identify a likely drug dealer and offer advice on what to do once you’ve confirmed your suspicions. We will also examine the laws around drugs, including what is and isn’t allowed and who is liable if those laws are broken on the premises you’re guarding.

Drug Dealers in Popular Culture

The sale of drugs has, of course, existed for thousands of years. However, in prehistory and antiquity drug use probably had at least some religious or spiritual connotations.

Nevertheless, recreational drug use dates back at least as far as Ancient Mesopotamia (and probably a lot further than that). Ancient Sumerians freely traded opium along with other commodities, while the ancient Egyptians prized blue water lotus flowers for their hallucinogenic properties (King Tutankhamun was even buried with some). These drugs were not illicit or illegal in their respective eras and traders would have bought and sold them openly.

Notable books concerning drug use and purchase include Thomas De Quincey’s autobiographical account ‘Confessions of an English Opium Eater’ (1821) and William Burroughs’ 1953 debut ‘Junkie: Confessions of an Unredeemed Drug Addict’.

In 1966, The Beatles released their ‘Revolver’ album, which featured a song called ‘Dr. Robert’. The song, inspired by real-life figure Dr. Robert Freymann, tells the story of a supposedly legitimate medical doctor who abuses his prescription pad in order to get his ‘patients’ any kind of drug they want. The song is notable for being one of the first times a drug dealer was depicted overtly, as well as in a generally positive light.

One year later, New York alternative band ‘The Velvet Underground’ released their debut album, which featured the songs ‘Waiting for the Man’ (which described a drug deal) and ‘Heroin’, the meaning of which ought to be self-explanatory. These songs were even more explicit and frank about illegal drugs and the people that use them.

The popular culture of the early 21st century is replete with examples of drug dealers. The 1983 gangster film ‘Scarface’ starring Al Pacino tells the story of Tony Montana, a Cuban refugee and petty criminal who becomes a wealthy drug baron in America. Today, ‘Scarface’ looms large in popular culture, with its themes and iconography being referenced in everything from other movies and TV shows to poster art, video games and even song lyrics.

Drug use and the sale of drugs are staples of gangster movies, with the sale of illicit materials often being contrasted with the basic assumptions of American capitalism as a way to comment upon society in general.

Another good example of these themes can be seen in the 2007 film ‘American Gangster’ starring Denzel Washington and Russell Crowe. This film also depicts drug dealing as a pathway to riches among the downtrodden and dispossessed.

‘American Gangster’s story, essentially, mirrors that of both ‘Scarface’ and any number of other movies of the genre, as well as, not incidentally, the typical experience of any addict. Drugs are initially seen as empowering and fun before becoming uncontrollable and eventually leading to the central character’s downfall.

The media treats street-level drug dealers, however, in a variety of different ways.

The 1993 movie ‘Trainspotting’ (an adaptation of the novel of same name by Irvine Welsh), starring Ewan McGregor, was praised for its frank and hard-hitting discussion of heroin addiction. The movie depicts a blurred line between using and dealing.

Perhaps popular culture’s best-loved drug dealers are Jay & Silent Bob. Beginning with the debut of comedy writer/director Kevin Smith, 1994’s ‘Clerks’, Jay (Jason Mewes) and his ‘hetero life-mate’ Silent Bob (Kevin Smith) appear in almost all of Smith’s movies, occasionally as central characters.

The pair, who mainly deal marijuana, are depicted as loveable, if crass, figures, who often attempt to resolve the issues of other characters via either heartfelt advice (‘Clerks’, ‘Chasing Amy’) or direct action (‘Mallrats’, ‘Dogma’). The pair appear to be stereotypical 1990’s-era drug dealers, usually peddling their wares outside the local convenience store, but their behaviour frequently upends audience expectations for comic effect.

The AMC TV series ‘Breaking Bad’, which began in 2008, depicts a grittier take on drug dealing. In the series, chemist Walter White (Bryan Cranston) is diagnosed with inoperable lung cancer and resorts to manufacturing and selling methamphetamines as a way of securing his family’s finances after his death. This decision leads him down a bad road, which sees the character becoming progressively darker as the show continues.

Similarly, the Starz black comedy series ‘Weeds’ (beginning in 2005) details the misadventures of widowed mother-of-two Nancy Botwin (Mary-Louise Parker), who takes to dealing marijuana as a way of supporting her family.

The legal drama series ‘Suits’, which began in 2011, features a drug dealer by the name of Trevor (Tom Lipinski), who is, at the series’ outset, best friend of main character Mike Ross (Patrick J. Adams). Unlike a stereotypical dealer, Trevor wears expensive suits and poses as a software developer to peddle his wares to a rich clientele. A failed drug deal involving Mike is the series’ inciting incident.

So, the portrayal of drug dealers in popular culture tends to vary, usually according to what drugs they are selling. Those selling marijuana are often depicted in a positive or comedic light (such as the episode of ‘Curb Your Enthusiasm’ wherein Larry David buys marijuana for his father), while those selling cocaine, heroin and other, harder drugs are usually seen as villainous, or at least more complicated, characters.

On television, drug dealers (that are not main characters) are usually seen as scruffy, but still attired in the urban fashions of the period (punk style in the 80’s and early 90’s, Hip Hop fashions from the mid-90’s – 2000’s, etc). They are traditionally young males.

Sadly, a disproportionate number of television drug dealers are cast as ethnic minorities, which does not reflect reality and only serves to fuel any number of negative stereotypes.

Such stylistic choices are part of a visual shorthand that encourages the audience to make a quick ‘snap judgement’ about a character in order not to waste any time setting up the joke or scene. So, if a young man, dressed in urban wear approaches a character, the audience will understand that he is likely a drug dealer. By contrast, if an older woman, dressed perhaps in an evening gown, approached the character, they would have to remark on the perceived incongruity of this alleged dealer in order for the scene to work.

These sorts of visual codes may be very useful for the TV and film industries, but they don’t do any favours to the security operative that is hoping to spot -and stop – a real-life drug deal taking place.

So, what are drug dealers like in real life?

Drug Dealers in Real Life

After surveying 243 self-identified drug dealers, researchers from the American Addiction Centers created the following profile of the ‘average’ drug dealer.

According to this fascinating and insightful study, a drug dealer is slightly more likely to be male than female (their numbers were 63% male and 37% female) and is likely to start dealing at around the age of 19 and stop by 23. Drug dealing is much rarer over the age of 30, but it definitely does happen.

The principal motivations for drug dealing are apparently needing money (40%), wanting extra money (29%) and the dealers desiring popularity with their peers (19%). Other motivations include the idea that drug dealers live glamorous lives (5%), peer pressure (5%) and supporting their own addictions (2%).

Most dealers got started through a friend (57%), or else through their own dealer (27%), while 10% stated that they were introduced to drug dealing through a family member.

The average drug dealer’s clientele is primarily students (34%) and working professionals (28%), although high school students (remember that this study is American, so these students could be as old as 18) also featured prominently. 2% even claimed to have dealt drugs to law enforcement offers.

The study revealed that 43% of the average drug dealer’s clients were considered by them to be addicts, but that only 11% of females and 9% of males denied their wares to those they considered at risk of death.

In hindsight, 61% said that they felt regret for their actions, while 39% were at peace with them. Only 45% admitted to feeling guilty, however, with a 55% majority stating that they did not. A small percentage stated that their actions had resulted in the deaths of some friends or clients.

The data is clear. Whilst a drug dealer is statistically slightly more likely to be young and male, they can (and do) look like anyone. Where TV’s drug dealers often wear loud clothes and openly publicise their products like foul-mouthed market vendors, real-life drug dealers are usually very adept at simply ‘blending in’ to their surroundings and not drawing undue attention to themselves.

Pop culture often assumes that drug dealers must resemble stereotypical drug users, however this is also rarely the case. A lot of dealers don’t use any drugs themselves and sell their products after working all day at a regular, 9-5 job.

Drug dealers can range from relatively innocuous-seeming people who sell ‘soft’ drugs to a small group of friends and/or family, to individuals of considerable wealth and influence, who sell, indirectly, to large numbers of people.

Some dealers sell prescription pain medication for those who are addicted to it, or experience chronic pain, some sell drugs that they consider harmless (but are, in fact, quite dangerous) and others do not consider themselves to be drug dealers at all.

Drug dealers can be any sex, gender, age, race, or class. So how can they be spotted?

How to Spot a Drug Deal

Knowing what we now know, we must consider that drug dealers are likely to be hard to spot. A drug deal, on the other hand, usually displays certain distinguishing characteristics that can be readily identified.

One trait common to most drug dealers is that they tend to set up in the same place each time they visit a venue. They do this so that customers know where to find them. A drug dealer’s preferred location is usually somewhere dark, slightly away from prying eyes, as well as a place that is likely to always be available. In most cases, dealers will not set themselves up in direct view of bar staff or door supervisors.

Be aware of any regular who sets themselves up in one specific place all or most of the time and is visited by multiple, seemingly unrelated, patrons or makes regular trips to the toilet. This person is very possibly a drug dealer.

Watch also for conspiratorial behaviour, such as two or more people huddling together as if sharing a secret. More experienced dealers will avoid this type of behaviour, but some dealers can still be identified this way.

Some dealers use accomplices known as ‘runners’ or ‘minders’ who actually carry the drugs and/or money. In this way, if the dealer is searched, security operatives or police will find nothing on them. A runner may not liaise with the dealer directly, but if a suspected dealer is visited several times by the same person, you may be inclined to search that person as well.

Dealers will often have a larger-than-average amount of cash about their person (although online payment methods are making this trait less common than it was). If a person has an abundance of cash on them (and you don’t work security in a strip club), this could be a sign that they are a dealer.

In person, dealers are often friendly and amiable, many are even charming. They are, after all, salespeople. With many customers that are probably nervous, it stands to reason that a dealer would want to be somewhat approachable.

Drug dealers are often very uncomfortable around the subject of drugs, however. When spoken to on the subject, many dealers will assume that they’ve been found out and will avoid the subject before leaving in a hurry. If you approach a suspected dealer and ask them about drugs while dressed in your uniform, their reaction can be a good indicator of either innocence or guilt.

What the Law Says

The main laws surrounding illegal drugs, at least for the purposes of this feature, are the Misuse of Drugs Act 1971 and the Licensing Act 2003. The Misuse of Drugs Act 1971 states that heavy penalties can be imposed upon any premises found to be permitting the sale or use of illegal drugs

The act, which was created to ensure the UK’s adherence to various international treaty conditions, made it illegal to possess, sell, offer to sell, or supply without charge any controlled drug or substance.

Oddly enough, despite the act’s title, the Misuse of Drugs Act 1971 does not cover the actual use of illegal drugs, nor does it immediately define which drugs it is referring to. Instead, the act defines 4 classes of controlled substances.

‘Class A’ drugs (heroin, cocaine, MDMA, LSD, methadone, methamphetamines, and magic mushrooms) are the most dangerous and therefore carry the harshest sentences under the act.

‘Class B’ drugs (amphetamines, codeine, barbiturates, ketamine, cannabis, and related cannabinoids) and ‘Class C’ drugs (anabolic steroids, diazepam, piperazines) are seen as less dangerous and carry lesser sentences. The ‘4th’ class is a temporary class, intended for more specific requirements than the broad classifications found elsewhere in the legislation.

Alcohol and tobacco are subject to separate legislation and are not affected by the terms of the act.

Under the terms of the Licensing Act 2003, if any licensed premises is found to be permitting the sale or use of illegal drugs, either interim steps toward the suspension of the license will be taken, or else the outright suspension of the license will occur.

A premises can also be closed under the Anti-Social Behaviour, Crime and Policing Act 2014.

The Misuse of Drugs Act 1971 was preceded by both the Dangerous Drugs Act 1964 (which dealt primarily with the use of cannabis and was itself preceded by the Dangerous Drug Act 1951) and the Medicines Act 1968, this second law primarily discussed the prescriptions, quality control and advertising of legal medicine. Prior to this, the laws around drugs and drug use were somewhat lax and insufficient.

Also of note is the Psychoactive Substances Act 2016, which was created to stop the spread of so-called ‘legal highs’. ‘Legal highs’ were drugs created to exploit loopholes in the terms of the Misuse of Drugs Act.

These legal drugs gained popularity in the 2000’s and 2010’s and were readily available from a variety of sources. Despite their easy availability, they were also very dangerous, killing almost 100 people in 2012 alone. The Psychoactive Substances Act was created to make their manufacture, sale and use illegal.

At present, Home Office guidelines (specific to, but not limited to raves and other ‘dance events’) allow for free cold water to be given to patrons as requested, the availability of a space to cool down and rest, monitoring of temperatures and air quality, provision of information and advice regarding drugs, and door staff to be trained to handle drug-related issues that may arise. 

Is the Law Effective?

According to the government’s latest figures, drug offences are on the rise in the UK. From 2020-21, drug-related offences jumped up by a massive 19% from 2019 – 20.

However, while this data may indicate a worsening trend, we must also consider the effect of the current coronavirus pandemic on the data. During lockdown, while the sale of illegal substances no doubt occurred, it would have been at least partially diminished, gaining more momentum once lockdowns were lifted.

Historically, British authorities have taken multiple approaches to preventing the sale and use of illegal drugs.

In 1954, the Metropolitan Police set up the Dangerous Drugs Office. It comprised of just 4 officers. In fact, a 1961 report on drug addiction in the UK concluded that

“the incidence of addiction to dangerous drugs is still very small… no cause to fear that any real increase is at present occurring”.

By 1963, however, the Metropolitan Police had learned that some doctors were overordering medicinal drugs and selling the surplus for personal profit, as well as overprescribing to addicts. After the number of arrests for drug-related offences began to climb, Parliament passed the Dangerous Drugs Act 1964 and the Medicines Act 1968.  

Further legislation was passed in the 1970’s and 1980’s, as new drugs began to be featured in the national discourse. Solvent abuse began in earnest in the 1980’s, which prompted the passage of the Intoxicating Substances (Supply) Act 1985, while barbiturates, which had been a serious problem since the mid-late 1970’s, were added to the Misuse of Drugs Act in 1984.

By 1985, MDMA was beginning to appear, claiming its first life in 1986. Police were given extra powers of search and interrogation, with particular emphasis on drug-related crimes by the Police and Criminal Evidence Act 1984.

1985’s Controlled Drug (Penalties) Act increased sentences for drug-related offences and the arrival of AIDS (which had existed since the 70’s, but was formally labelled an epidemic  in the 80’s) issued a public crackdown on needle sharing. Accordingly, the Drug Trafficking Offences Act 1986 came into effect in 1987. This act was partially intended to help recover the profits from drug trafficking. 

As we have seen, the issue of drugs exploded between the 1960’s and the 1990’s. By 1994, drug use was being seen as a global epidemic. The government published its ‘green paper’, titled ‘Tackling Drugs Together: A consultation document on a strategy for England 1995–1998′. This document outlined a ‘new approach to strategic thinking on drugs issues’, with an emphasis on reducing the availability of illegal drugs and keeping communities safer from drug-related offences.

The government also passed the Criminal Justice and Public Order Act 1994, which attempted to control drug use in prisons, as well as at raves.

Some of these measures have been reasonably effective, others appear not to have worked at all. However, the problem continues to persist, at times worsening.

The law is certainly effective when it comes to arresting and detaining some dealers, but the fact that drug use continues to be so persistent and prevalent shows that no measure has ever been 100% successful.

Critics of the Misuse of Drugs Act 1971, for example, have suggested that the classification system is inadequate because it does not consider the relative dangers of the drugs it classifies. This argument was key to the decision to reclassify cannabis as a ‘Class C’ drug in 2004. Nevertheless, the drug was moved back to ‘Class B’ in 2009.

In this case, the law would appear to be somewhat out-of-step with public opinion. The Liberal Democrat Party has supported the legalisation and taxation of Cannabis since 2015, making them the first mainstream British political party to do so.

Public support has also drifted more towards sympathy with hard-drug users in recent years, as mental health issues and the nature of addiction become better understood by the public.

Britain’s anti-drug policies and legislation may appear harsh to some, but there are many other countries that are far less tolerant. In Malaysia, China, Vietnam, Iran, Thailand, Saudi Arabia, Singapore, Indonesia and The Philippines, drug dealers can be (and often are) executed by the state.  

Despite these brutal punishments, drug trafficking, dealing and use still occurs in all these countries. According to the U.N., domestic drug abuse in Vietnam has risen sharply since the 1990’s, while a 2020 review found that mental health conditions, arising from chronic drug use, are a problem in Saudi Arabia.

In addition to heroin and opium use, Thailand is currently facing the rise of a popular street drug known as ‘Yaba’, which is a mixture of caffeine and methamphetamine.

The notion that harsher punishments for crimes will somehow eliminate those crimes from occurring is a faulty one. It has been tried – and has failed, many times throughout history. The death penalty for murder, for example, does not prevent murder.

Is the law effective? Yes and no. As with drugs themselves and basically everything else, it depends on the individual.

Preventing Drug Dealing/Use on the Premises

There are a number of preventative methods that a bar, pub, club or venue can take if it wants to actively discourage drug dealers. Door supervisors are the first line of defence against these activities, so it is of vital importance that they remain vigilant at all times.

Firstly, we advise that proprietors keep their venues clean and tidy, with security cameras in clear view. A drug dealer is probably looking for a place with lax security. If it looks like the management can’t be bothered to clean up at the end of the night, a drug dealer may well feel more confident about ‘setting up shop’ there.

Ensuring that all CCTV, alarms, and other security equipment is up-to-date and functioning well is also a great way to deter drug dealers. 

We also recommend putting up notices that drug dealing on the premises will not be tolerated under any circumstances.  The venue should create a drugs policy and make every employee (including door staff) aware of it. All signage should reflect this policy.

Joining a local ‘Pubwatch‘ scheme is a great way for venues to share intel on specific troublemakers and get a sense of how widespread the problem is in the local area.

It is advisable also to always refuse entry to any known or suspected drug dealers. This can be part of the venue’s drugs policy. For example, it can be venue policy that any patron caught dealing drugs on the premises may be the recipient of a ‘lifetime ban’ and reported to other venues as well.

We also suggest that all security operatives keep an eye out for signs of drug use. Signs of drug use can include payment with tightly wound banknotes (occasionally showing a small amount of powder or blood at the edges), traces of powder left on surfaces (particularly in restrooms), as well as other ‘tell-tale trash’ left behind by drug users, such as small ‘sealie’ bags, torn beermats, empty pill bottles and sweet or chewing gum wrappers.

If the toilets turn up incongruous items such as burned spoons or tinfoil, drinking straws, lighters, razor blades, make-up mirrors, small squares of cling film, syringes or discarded tubes of glue, the venue has probably been visited by a drug user. Surfaces that have been wiped entirely clean before closing time can also be a giveaway.

You may also be alert to the signs of a person using drugs at the venue. These can include the more obvious behaviours (vacant expression, a sense of the person not truly being ‘present’, bloodshot eyes, dilated pupils, excessive chattering, giggling or noise for example), to ordering excessive amounts of water, sporting white marks around the nostrils, and appearing to be either hyperactive or extremely lethargic.

If your venue or premises appears to have a serious problem with drug dealing and/or use, we recommend contacting local police or drug squads. If these problems persist, the venue could lose its license, or be closed entirely. More importantly, lives could even be at stake.

A police licensing officer who has been informed of a potential situation at the venue will be far more likely to show compassion and sympathy to a venue that reaches out for help than they will if they must investigate it of their own volition. Where possible, we advise security staff and venue proprietors to liaise with police at regular intervals.

Door searches, though not always popular, may also be necessary in the more severe cases.

Of course, all drug-related instances, even small ones, must be recorded in the venue’s incident books and, where appropriate, referred to police.

Stopping a drug deal may seem like a small victory. Indeed, many security operatives simply deem it ‘part of the job’ and don’t give it much attention beyond that. However, there is no such thing as an inconsequential action. As the zen proverb has it, “the man who would move a mountain begins by carrying away small stones”.

Each drug deal thwarted contributes toward making Britain’s streets, establishments, and businesses safer, which in turn helps to ensure the safety of people everywhere – and that, more than anything else, is the reason security operatives do what they do in the first place.

Source: Drug Dealers: Dealing with Drugs and Dealers – Working The Doors

Filed under: Crime/Violence/Prison,Drug use-various effects,Economic,Legal Sector,Political Sector :

Source: 20-Reasons-to-Vote-NO-in-2020-SAM-VERSION-Cannabis.pdf (saynopetodope.org.nz) May 2020

Filed under: Cannabis/Marijuana,Crime/Violence/Prison,Drug use-various effects,Drugs and Accidents,Economic,Environment,Global Drug Legalisation Efforts,Legal Sector,Political Sector,Social Affairs :

In what is sure to be a controversial finding among cannabis users and proponents, a review of existing research published this week in The Lancet Psychiatry suggests that a single dose of THC may induce a variety of psychiatric symptoms associated with schizophrenia and other psychiatric disorders.

According to a news release issued by The Lancet on March 17:

A single dose of the main psychoactive component in cannabis, tetrahydrocannabinol (THC), can induce a range of psychiatric symptoms, according to results of a systematic review and meta-analysis of 15 studies including 331 people with no history of psychotic or other major psychiatric disorders, published in The Lancet Psychiatry journal.

The study was funded by the Medical Research Council and was conducted by researchers from Kings College London, South London and the Maudsley NHS Foundation Trust, Imperial College London, Leiden University Medical Hospital, Yale University School of Medicine, Connecticut Mental Health Center, and VA Connecticut Healthcare System.

The study also notes that these psychiatric symptoms are not associated with cannabidiol (CBD), one of the other major active compounds in cannabis. The authors reviewed four studies examining CBD’s effects on the development of the same psychiatric symptoms, and no significant differences were found between the effects of CBD and the effects of a placebo. “In studies that focused on whether CBD counters THC-induced symptoms, one study identified reduced symptoms, using a modest sample, but three larger studies failed to replicate this finding.”

The aforementioned news release quotes King’s College professor Oliver Howes as saying, “As the THC-to-CBD ratio of street cannabis continues to increase, it is important to clarify whether these compounds can cause psychotic symptoms. Our finding that THC can temporarily induce psychiatric symptoms in healthy volunteers highlights the risks associated with the use of THC-containing cannabis products. This potential risk should be considered in discussions between patients and medical practitioners thinking about using cannabis products with THC. This work will also inform regulators, public health initiatives, and policy makers considering the medical use of THC-containing cannabis products or their legalisation for recreational use.” 

There’s an important distinction to note here. Although the researchers found that a dose of THC—which they say is roughly equivalent to a single joint—can induce symptoms that mimic those of certain psychiatric disorders, THC does not in fact cause said disorders in users. 

This will come as little surprise to cannabis users, who are well aware from decades of anecdotal evidence that smoking a joint can make some people a little paranoid, but it has certainly never made anyone schizophrenic.

To put things in perspective, consider that in a commentary he wrote for the Straight last August, author and activist Dana Larsen noted that “every analysis of relative drug harms lists cannabis as one of the safest psychoactive substances there is.”

You can read the paper, which is title “Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis”, at the Lancet Psychiatry website.

Source:  https://www.straight.com/cannabis/1374471/review-studies-suggests-thc-cannabis-could-induce-psychotic-symptoms-healthy-people  19th March 2020

Filed under: Brain and Behaviour,Cannabis/Marijuana :

Abstract

Objectives: Many reports exist of the cardiovascular toxicity of smoked cannabis but none of arterial stiffness measures or vascular age (VA). In view of its diverse toxicology, the possibility that cannabis-exposed patients may be ageing more quickly requires investigation.

Design: Cross-sectional and longitudinal, observational. Prospective.

Setting: Single primary care addiction clinic in Brisbane, Australia.

Participants: 11 cannabis-only smokers, 504 tobacco-only smokers, 114 tobacco and cannabis smokers and 534 non-smokers.

Exclusions: known cardiovascular disease or therapy or acute exposure to alcohol, amphetamine, heroin or methadone.

Intervention: Radial arterial pulse wave tonometry (AtCor, SphygmoCor, Sydney) performed opportunistically and sequentially on patients between 2006 and 2011.

Main outcome measure: Algorithmically calculated VA.

Secondary outcomes: other central haemodynamic variables.

Results: Differences between group chronological ages (CA, 30.47±0.48 to 40.36±2.44, mean±SEM) were controlled with linear regression. Between-group sex differences were controlled by single-sex analysis. Mean cannabis exposure among patients was 37.67±7.16 g-years. In regression models controlling for CA, Body Mass Index (BMI), time and inhalant group, the effect of cannabis use on VA was significant in males (p=0.0156) and females (p=0.0084). The effect size in males was 11.84%. A dose-response relationship was demonstrated with lifetime exposure (p<0.002) additional to that of tobacco and opioids. In both sexes, the effect of cannabis was robust to adjustment and was unrelated to its acute effects. Significant power interactions between cannabis exposure and the square and cube of CA were demonstrated (from p<0.002).

Conclusions: Cannabis is an interactive cardiovascular risk factor (additional to tobacco and opioids), shows a prominent dose-response effect and is robust to adjustment. Cannabis use is associated with an acceleration of the cardiovascular age, which is a powerful surrogate for the organismal-biological age. This likely underlies and bi-directionally interacts with its diverse toxicological profile and is of considerable public health and regulatory importance.

Keywords: Accelerated aging; Biological age; Biomarkers of aging; Cannabis and aging.

Source: Cannabis exposure as an interactive cardiovascular risk factor and accelerant of organismal ageing: a longitudinal study – PubMed (nih.gov) November 2016

Filed under: Cannabis/Marijuana,Health,Nicotine :

A meta-analysis of all studies worldwide showing association between marijuana use and schizophrenia:

Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319–328.
http://dirwww.colorado.edu/alcohol/downloads/Cannabis_and_behavior.pdf

“There was an increased risk of any psychotic outcome in individuals who had ever used cannabis…with greater risk in people who used cannabis most frequently. There is now sufficient evidence to warn young people that using cannabis could increase their risk of
developing a psychotic illness later in life.”

The most recent study conducted in the United States (Columbia University, New York), showing a high risk (odds ratio, “OR”) for schizophrenia spectrum disorders, particularly in those who become cannabis-dependent:

Davis GP, Compton MT, Wang S, Levin FR, Blanco C. Association between cannabis use, psychosis, and schizotypal personality disorder: findings from the National Epidemiologic Survey on Alcohol and Related Conditions. Schizophr Res. 2013 Dec;151(1-3):197-202.
“There was a similar dose-response relationship between the extent of cannabis use and schizotypal personality disorder (OR=2.02 for lifetime cannabis use, 95% CI 1.69-2.42; OR=2.83 for lifetime cannabis abuse, 95% CI 2.33-2.43; OR=7.32 for lifetime cannabis dependence, 95% CI 5.51-9.72). Likelihood of individual schizotypal features increased significantly with increased extent of cannabis use in a dose-dependent manner.”

Studies that corrected for general genetic background effects and many non-cannabis environmental variables by comparing siblings. The risk ratios are somewhat lower than general population studies, because genetic predisposition is more or less controlled for:

McGrath J, Welham J, Scott J, Varghese D, Degenhardt L, Hayatbakhsh MR, Alati R, Williams GM, Bor W, Najman JM. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch Gen Psychiatry. 2010; 67(5):440-7.
“Longer duration since first cannabis use was associated with multiple psychosis-related outcomes in young adults… the longer the duration since first cannabis use, the higher the risk of psychosis-related outcomes…
Compared with those who had never used cannabis, young adults who had 6 or more years since first use of cannabis (i.e., who commenced use when around 15 years or younger) were twice as likely to develop a nonaffective psychosis…
This study provides further support for the hypothesis that early cannabis use is a risk-modifying factor for psychosis-related outcomes in young adults.”

Giordano GN, Ohlsson H, Sundquist K, Sundquist J, Kendler KS. The association between cannabis abuse and subsequent schizophrenia: a Swedish national co-relative control study.
Psychol Med. 2014 Jul 3:1-8. [Epub ahead of print]
http://journals.cambridge.org/download.php?file=%2FPSM%2FS0033291714001524a.pdf&code=79f795824a92c8eead870197ef071dd8

“Allowing 7 years from initial CA registration to later diagnosis, the risk for schizophrenia in discordant full sibling pairs remained almost twofold….The results of this study therefore lend support to the etiologic hypothesis, that CA is one direct cause of later schizophrenia.”

Those diagnosed with schizophrenia who also use recreational drugs are much more likely to be violent, including those who use cannabis:

Fazel S, Långström N, Hjern A, Grann M, Lichtenstein P. Schizophrenia, substance abuse, and violent crime. JAMA. 2009 May 20;301(19):2016-23.
“The risk was mostly confined to patients with substance abuse comorbidity (of whom 27.6% committed an offense), yielding an increased risk of violent crime among such patients (adjusted OR, 4.4; 95% CI,3.9-5.0), whereas the risk increase was small in schizophrenia patients without substance abuse comorbidity (8.5% of whom had at least 1 violent offense; adjusted OR,1.2; 95% CI, 1.1-1.4; P<0.001 for interaction).”

Fazel S, Gulati G, Linsell L, Geddes JR, Grann M. Schizophrenia and violence: systematic review and meta-analysis. PLoS Med. 2009 Aug;6(8):e1000120. doi: 10.1371/journal.pmed.1000120. Epub 2009 Aug 11.
“The effect of comorbid substance abuse was marked with….. an OR of 8.9” (as compared to the general population)

Arseneault L, Moffitt TE, Caspi A, Taylor PJ, Silva PA. Mental disorders and violence in a total birth cohort: results from the Dunedin Study. Arch Gen Psychiatry. 2000;57(10):979-86.
“for having more than two of these disorders at once…..the OR (odds ratio for violence) was, …..for marijuana dependence plus schizophrenia spectrum disorder, 18.4”

Harris AW, Large MM, Redoblado-Hodge A, Nielssen O, Anderson J, Brennan J. Clinical and cognitive associations with aggression in the first episode of psychosis. Aust N Z J Psychiatry. 2010 Jan;44(1):85-93.
‘The use of cannabis with a frequency of more than fourfold in the previous month was the only factor that was found to be associated with serious aggression’

Self-report of psychotic symptoms by otherwise healthy users (12% to 15%):

Thomas H. A community survey of adverse effects of cannabis use. Drug Alcohol Depend. 1996 Nov;42(3):201-7.
“This survey estimates the frequency of various adverse effects of the use of the drug cannabis. A sample of 1000 New Zealanders aged 18-35 years were asked to complete a self-administered questionnaire on cannabis use and associated problems. The questionnaire was derived from criteria for the identification of cannabis abuse which are analagous to criteria commonly used to diagnose alcoholism. Of those who responded 38% admitted to having used cannabis. The most common physical or mental health problems, experienced by 22% of users were acute anxiety or panic attacks following cannabis use. Fifteen percent reported psychotic symptoms following use.”

Smith MJ, Thirthalli J, Abdallah AB, Murray RM, Cottler LB. Prevalence of psychotic symptoms in substance users: a comparison across substances. Compr Psychiatry. 2009 May-Jun;50(3):245-50. doi: 10.1016/j.comppsych.2008.07.009. Epub 2008 Sep 23.
“Among all users of substances without a diagnosis of abuse or dependence, cannabis users reported the highest prevalence of psychotic symptoms (12.4%).”

Barkus EJ, Stirling J, Hopkins RS, Lewis S.. Cannabis-induced psychosis-like experiences are associated with high schizotypy Psychopathology 2006;39(4):175-8.
“In the sample who reported ever using cannabis (72%) the means for the subscales from the CEQ were as follows: ……Psychotic-Like Experiences (12.98%).”

Rates of psychotic symptoms in those with cannabis dependence as compared to non-dependent users and nonusers:

Fergusson DM, Horwood LJ, Swain-Campbell NR. Cannabis dependence and psychotic symptoms in young people. Psychol Med. 2003 Jan;33(1):15-21.
“Young people meeting DSM-IV criteria for cannabis dependence had elevated rates of psychotic symptoms at ages 18 (rate ratio = 3.7; 95% CI 2.8-5.0; P < 0.0001) and 21 (rate ratio = 2.3; 95% CI 1.7-3.2; P < 0.0001).”

Smith MJ, Thirthalli J, Abdallah AB, Murray RM, Cottler LB. Prevalence of psychotic symptoms in substance users: a comparison across substances. Compr Psychiatry. 2009 May-Jun;50(3):245-50. doi: 10.1016/j.comppsych.2008.07.009. Epub 2008 Sep 23.
“more than half of the respondents who were dependent on cocaine (80%), cannabis (63.5%), amphetamines (56.1%), and opiates (53.1%) reported psychotic symptoms. Among all users of substances without a diagnosis of abuse or dependence, cannabis users reported the highest prevalence of psychotic symptoms (12.4%)……. There was also a marked increase in the risk for psychotic symptoms when dependence became moderate or severe for cannabis (OR=25.1, OR=26.8; respectively).”

Studies on the psychotomimetic properties of THC administered to healthy individuals in the clinic:

D’Souza DC, Perry E, MacDougall L, Ammerman Y, Cooper T, Wu YT, Braley G, Gueorguieva R, Krystal JH. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology. 2004 Aug;29(8):1558-72.
“∆-9-THC (1) produced schizophrenia-like positive and negative symptoms; (2) altered perception;(3) increased anxiety; (4) produced euphoria; (5) disrupted immediate and delayed word recall, sparing recognition recall; (6) impaired performance on tests of distractibility, verbal fluency, and working memory (7) did not impair orientation; (8) increased plasma cortisol. These data indicate that D-9-THC produces a broad range of transient symptoms, behaviors, and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses.”

Morrison PD, Nottage J, Stone JM, Bhattacharyya S, Tunstall N, Brenneisen R, Holt D, Wilson D, Sumich A, McGuire P, Murray RM, Kapur S, Ffytche DH. Disruption of frontal θ coherence by ∆9-tetrahydrocannabinol is associated with positive psychotic symptoms. Neuropsychopharmacology. 2011;;36(4):827-36.
“Compared with placebo, THC evoked positive and negative psychotic symptoms, as measured by the positive and negative syndrome scale (p<0.001)…… The results reveal that the pro-psychotic effects of THC might be related to impaired network dynamics with impaired communication between the right and left frontal lobes.”

Bhattacharyya S, Crippa JA, Allen P, Martin-Santos R, Borgwardt S, Fusar-Poli P, Rubia K, Kambeitz J, O’Carroll C, Seal ML, Giampietro V, Brammer M, Zuardi AW, Atakan Z, McGuire PK. Induction of psychosis by ∆9-tetrahydrocannabinol reflects modulation of prefrontal and striatal function during attentional salience processing. Arch Gen Psychiatry. 2012 Jan;69(1):27-36. doi: 10.1001/archgenpsychiatry.2011.161.
“Pairwise comparisons revealed that 9-THC significantly increased the severity of psychotic symptoms compared with placebo (P<.001) and CBD (P<.001).”,

Freeman D, Dunn G, Murray RM, Evans N, Lister R, Antley A, Slater M, Godlewska B, Cornish R, Williams J, Di Simplicio M, Igoumenou A, Brenneisen R, Tunbridge EM, Harrison PJ, Harmer CJ, Cowen P, Morrison PD. How Cannabis Causes Paranoia: Using the Intravenous Administration of ∆9-Tetrahydrocannabinol (THC) to Identify Key Cognitive Mechanisms Leading to Paranoia. Schizophr Bull. 2014 Jul 15. pii: sbu098. [Epub ahead of print]
“THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity.”

For data on dose-response (a very large study by Zammit et al., and another by van Os et al.) and the greater risk for psychosis posed by high strength marijuana (DiForti et al.):

Zammit S, Allebeck P, Andreasson S, Lundberg I, Lewis G, 2002, Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study. BMJ. 2002 Nov 23;325(7374):1199. http://www.bmj.com/content/325/7374/1199.full.pdf
“We found a dose dependent relation between frequency of cannabis use and risk of schizophrenia, with an adjusted odds ratio for linear trend across the categories of frequency of cannabis use used in this study of 1.2 (1.1 to 1.4, P < 0.001). The adjusted odds ratio for subjects with a history of heaviest use of cannabis ( > 50 occasions) was 3.1 (1.7 to 5.5)………………Cannabis use is associated with an increased risk of
developing schizophrenia, consistent with a causal relation. This association is not explained by use of other psychoactive drugs or personality traits relating to social integration.”

van Os J, Bak M, Hanssen M, Bijl RV, de Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol. 2002 Aug 15;156(4):319-27.
“…..further evidence supporting the hypothesis of a causal relation is demonstrated by the existence of a dose-response relation.. between cumulative exposure to cannabis use and the psychosis outcome……. About 80 percent of the psychosis outcome associated with exposure to both cannabis and an established vulnerability to psychosis was attributable to the synergistic action of these two factors. This finding indicates that, of the subjects exposed to both a vulnerability to psychosis and cannabis use, approximately 80 percent had the psychosis outcome because of the combined action of the two risk factors and only about 20 percent because of the action of either factor alone.”

DiForti M, Morgan C, Dazzan P, Pariante C, Mondelli V, Marques TR, Handley R, Luzi S, Russo M, Paparelli A, Butt A, Stilo SA, Wiffen B, Powell J, Murray RM. High-potency cannabis and the risk of psychosis. Br J Psychiatry. 2009,195(6):488-91.
“78% (n = 125) of the cases group preferentially used sinsemilla (skunk) compared with only 31% (n = 41) of the control group (unadjusted OR= 8.1, 95% CI 4.6–13.5). This association was only slightly attenuated after controlling for potential confounders (adjusted OR= 6.8, 95% CI 2.6–25.4)………. Our most striking finding is that patients with a first episode of psychosis preferentially used high-potency cannabis preparations of the sinsemilla (skunk) variety…… our results suggest that the potency and frequency of cannabis use may interact in further increasing the risk of psychosis.”

DiForti M, Marconi A, Carra E, Fraietta S, Trotta A, Bonomo M, Bianconi F, Gardner-Sood P, O’Connor J, Russo M, Stilo SA, Marques TR, Mondelli V, Dazzan P, Pariante C, David AS, Gaughran F, Atakan Z, Iyegbe C, Powell J, Morgan C, Lynskey M, Murray RM. Proportion of
patients in south London with first-episode psychosis attributable to use of high potency cannabis: a case-control study. Lancet Psychiatry, online February 18, 2015, http://dx.doi.org/10.1016/S2215-0366(14)00117-5.
“In the present larger sample analysis, we replicated our previous report and showed that the highest probability to suffer a psychotic disorder is in those who are daily users of high potency cannabis. Indeed, skunk use appears to contribute to 24% of cases of first episode psychosis in south London. Our findings show the importance of raising awareness among young people of the risks associated with the use of high-potency cannabis. The need for such public education is emphasised by the worldwide trend of liberalisation of the legal constraints on cannabis and the fact that high potency varieties are becoming much more widely available.”

For data on percent of those with marijuana-induced psychosis who go on to receive a diagnosis of a schizophrenia spectrum disorder:

Arendt M, Mortensen PB, Rosenberg R, Pedersen CB, Waltoft BL. Familial predisposition for psychiatric disorder: comparison of subjects treated for cannabis-induced psychosis and schizophrenia. Arch Gen Psychiatry. 2008;65(11):1269-74. http://archpsyc.ama-assn.org/cgi/reprint/65/11/1269
“Approximately half of the subjects who received treatment of a cannabis induced psychosis developed a schizophrenia spectrum disorder within 9 years after treatment…… The risk of schizophrenia after a cannabis-induced psychosis is independent of familial predisposition……. cannabis-induced psychosis may not be a valid diagnosis but an early marker of schizophrenia……. Psychotic symptoms after cannabis
use should be taken extremely seriously.”

Niemi-Pynttäri JA, Sund R, Putkonen H, Vorma H, Wahlbeck K, Pirkola SP. Substance-induced psychoses converting into schizophrenia: a register-based study of 18,478 Finnish inpatient cases. J Clin Psychiatry. 2013 74(1):e94-9.
“Eight-year cumulative risk to receive a schizophrenia spectrum diagnosis was 46% for persons with a diagnosis of cannabis-induced psychosis ….. chances for amphetamine-, hallucinogen-, opioid-, sedative- and alcohol-induced (schizophrenia spectrum diagnoses) were 30%, 24%, 21%, and 5% respectively.”

For cause and effect (which comes first: psychosis or marijuana use):
Arseneault L, Cannon M, Poulton R, Murray R, Caspi A, Moffitt TE, 2002, Cannabis use in
adolescence and risk for adult psychosis: longitudinal prospective study.BMJ. 2002 Nov 23;325(7374):1212-3.
“Firstly, cannabis use is associated with an increased risk of experiencing schizophrenia symptoms, even after psychotic symptoms preceding the onset of cannabis use are controlled for, indicating that cannabis use is not secondary to a pre-existing psychosis. Secondly, early cannabis use (by age 15) confers greater risk for schizophrenia outcomes than later cannabis use (by age 18). Thirdly, risk was specific to cannabis use, as opposed to use of other drugs….”

Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. BMJ. 2005;330:11–15. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC539839/pdf/bmj33000011.pdf
“Exposure to cannabis during adolescence and young adulthood increases the risk of psychotic symptoms later in life. Cannabis use at baseline increased the cumulative incidence of psychotic symptoms at follow up four years later…but has a much stronger effect in those with evidence of predisposition for psychosis……….Predisposition for psychosis at baseline did not significantly predict cannabis use four years later..”

and also:

Kuepper R, van Os J, Lieb R, Wittchen HU, Höfler M, Henquet C. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study.BMJ. 2011 Mar 1;342: d738 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047001/pdf/bmj.d738.pdf
“In individuals who had no reported lifetime psychotic symptoms and no reported lifetime cannabis use at baseline, incident cannabis use over the period from baseline to T2 increased the risk of later incident psychotic symptoms over the period from T2 to T3 (adjusted odds ratio 1.9, 95% confidence interval 1.1 to 3.1; P=0.021)…………There was no evidence for self medication effects, as psychotic experiences at T2 did not predict incident cannabis use between T2 and T3 (0.8, 0.6 to 1.2; P=0.3).”

For data on those who quit using when psychotic symptoms develop (further evidence against self-medication):

Fergusson DM, Horwood LJ, Ridder EM. Tests of causal linkages between cannabis use and psychotic symptoms. Addiction. 2005;100(3):354-66.

For degree of risk relative to other drugs:

Niemi-Pynttäri JA, Sund R, Putkonen H, Vorma H, Wahlbeck K, Pirkola SP. Substance-induced psychoses converting into schizophrenia: a register-based study of 18,478 Finnish inpatient cases. J Clin Psychiatry. 2013 74(1):e94-9.
“Eight-year cumulative risk to receive a schizophrenia spectrum diagnosis was 46% for persons with a diagnosis of cannabis-induced psychosis ….. chances for amphetamine-, hallucinogen-, opioid-, sedative- and alcohol-induced (schizophrenia spectrum diagnoses) were 30%, 24%, 21%, and 5% respectively.”

Smith MJ, Thirthalli J, Abdallah AB, Murray RM, Cottler LB. Prevalence of psychotic symptoms in substance users: a comparison across substances. Compr Psychiatry. 2009 May-Jun;50(3):245-50. doi: 10.1016/j.comppsych.2008.07.009. Epub 2008 Sep 23.
“more than half of the respondents who were dependent on cocaine (80%), cannabis (63.5%), amphetamines (56.1%), and opiates (53.1%) reported psychotic symptoms. Among all users of substances without a diagnosis of abuse or dependence, cannabis users reported the highest prevalence of psychotic symptoms (12.4%)……. There was also a marked increase in the risk for psychotic symptoms when dependence became moderate or severe for cannabis (OR=25.1, OR=26.8; respectively).”

Another angle on the potential confound of self-medication: genetic predisposition for schizophrenia does not predict cannabis use:

Veling W, Mackenbach JP, van Os J, Hoek HW. Cannabis use and genetic predisposition for schizophrenia: a case-control study. Psychol Med. 2008 Sep;38(9):1251-6. Epub 2008 May 19.
“BACKGROUND: Cannabis use may be a risk factor for schizophrenia. RESULTS: Cannabis use predicted schizophrenia [adjusted odds ratio (OR) cases compared to general hospital controls 7.8, 95% confidence interval (CI) 2.7-22.6; adjusted OR cases compared to siblings 15.9 (95% CI 1.5-167.1)], but genetic predisposition for schizophrenia did not predict cannabis use [adjusted OR intermediate predisposition
compared to lowest predisposition 1.2 (95% CI 0.4-3.8)].”

For data on potential benefits of cessation:

González-Pinto A, Alberich S, Barbeito S, Gutierrez M, Vega P, Ibáñez B, Haidar MK, Vieta E, Arango C. Cannabis and first-episode psychosis: different long-term outcomes depending on continued or discontinued use. Schizophr Bull. 2011 May;37(3):631-9. Epub 2009 Nov 13. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080669/pdf/sbp126.pdf
“OBJECTIVE: To examine the influence of cannabis use on long-term outcome in patients with a first psychotic episode, comparing patients who have never used cannabis with (a) those who used cannabis before the first episode but stopped using it during follow-up and (b) those who used cannabis both before the first episode and during follow-up….. CONCLUSION: Cannabis has a deleterious effect, but stopping use after the first psychotic episode contributes to a clear improvement in outcome. The positive effects of stopping cannabis use can be seen more clearly in the long term.”

Kuepper R, van Os J, Lieb R, Wittchen HU, Höfler M, Henquet C. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study.BMJ. 2011 Mar 1;342: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047001/pdf/bmj.d738.pdf
“The finding that longer exposure to cannabis was associated with greater risk for persistence of psychotic experiences is in line with an earlier study showing that continued cannabis use over time increases the risk for psychosis in a dose-response fashion. This is also in agreement with the hypothesis that a process of sensitisation might underlie emergence and persistence of psychotic experiences as an indicator of liability to psychotic disorder.”

For data on marijuana use resulting in an earlier age of onset of schizophrenia (suggestive of causality), see Dragt et al. and a meta-analysis (see Large et al.,); also: a very extensive (676 schizophrena patients) and therefore more statistically powered analysis (see DeHert paper); two papers showing that the age-of-onset effect may be specific to those without a family history (see Scherr et al. and Leeson et al., papers); two studies that evaluate the age of onset specific to gender (Veen et al. and Compton et al. ) which is important because comparing across genders can be confounded by the greater tendency of males to engage in risky behavior (the conclusions are not the same in terms of gender; the gender distribution was slightly better in the Veen et al. study) and finally, two papers of relevance to specificity of age of onset effect to cannabis, a meta-analysis of published studies on age of onset that shows another drug of abuse (tobacco) is not associated with
a decreased age of onset (Myles et al.) and a study showing that ecstasy, LSD, stimulants, or sedatives did not have an effect to lower age of onset whereas cannabis use did (Barnes et al.) :

Large M, Sharma S, Compton MT, Slade T, Nielssen O. Cannabis Use and Earlier Onset of Psychosis: A Systematic Meta-analysis. Arch Gen Psychiatry. 2011 68(6):555-61. http://www.ncbi.nlm.nih.gov/pubmed/21300939
“The results of meta-analysis provide evidence for a relationship between cannabis use and earlier onset of psychotic illness, and they support the hypothesis that cannabis use plays a causal role in the development of psychosis in some patients. The results suggest the need for renewed warnings about the potentially harmful effects of cannabis.”

Dragt S, Nieman DH, Schultze-Lutter F, van der Meer F, Becker H, de Haan L, Dingemans PM, Birchwood M, Patterson P, Salokangas RK, Heinimaa M, Heinz A, Juckel G, Graf von Reventlow H, French P, Stevens H, Ruhrmann S, Klosterkötter J, Linszen DH; on behalf of the EPOS group.Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis. Acta Psychiatr Scand. 2011 Aug 29. doi: 10.1111/j.1600-0447.2011.01763.x. [Epub ahead of print]
“Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis. Objective: Numerous studies have found a robust association between cannabis use and the onset of psychosis. Nevertheless, the relationship between cannabis use and the onset of early (or, in retrospect, prodromal) symptoms of psychosis remains unclear. The study focused on investigating the relationship between cannabis
use and early and high-risk symptoms in subjects at clinical high risk for psychosis. Results: Younger age at onset of cannabis use or a cannabis use disorder was significantly related to younger age at onset of six symptoms (0.33 < r(s) < 0.83, 0.004 < P < 0.001). Onset of cannabis use preceded symptoms in most participants. Conclusion: Our results provide support that cannabis use plays an important role in the development of psychosis in vulnerable individuals.”

De Hert M, Wampers M, Jendricko T, Franic T, Vidovic D, De Vriendt N, Sweers K, Peuskens J, van Winkel R.Effects of cannabis use on age at onset in schizophrenia and bipolar disorder. Schizophr Res. 2011 Mar;126(1-3):270-6.

“BACKGROUND: Cannabis use may decrease age at onset in both schizophrenia and bipolar disorder, given the evidence for substantial phenotypic and genetic overlap between both disorders….RESULTS:… Both cannabis use and a schizophrenia diagnosis predicted earlier age at onset. There was a significant interaction between cannabis use and diagnosis, cannabis having a greater effect in bipolar patients….DISCUSSION:…. Our results suggest that cannabis use is associated with a reduction in age at onset in both schizophrenic and bipolar patients. This reduction seems more pronounced in the bipolar group than in the schizophrenia group: the use of cannabis reduced age at onset by on average 8.9 years in the bipolar group, as compared to an average predicted reduction of 1.5 years in the schizophrenia group.”

Scherr M, Hamann M, Schwerthöffer D, Froböse T, Vukovich R, Pit schel-Walz G, Bäuml J.. Environmental risk factors and their impact on the age of onset of schizophrenia: Comparing familial to non-familial schizophrenia. Nord J Psychiatry. 2011 Aug 31. [Epub ahead of print]
“Background and aims: Several risk factors for schizophrenia have yet been identified. The aim of our study was to investigate how certain childhood and adolescent risk factors predict the age of onset of psychosis in patients with and without a familial component (i.e. a relative with schizophrenia or schizoaffective disorder). Results: Birth complications and cannabis abuse are predictors for an earlier onset of schizophrenia in patients with non-familial schizophrenia. No environmental risk factors for an earlier age of onset in familial schizophrenia have been identified.”

Leeson VC, Harrison I, Ron MA, Barnes TR, Joyce EM. The Effect of Cannabis Use and Cognitive Reserve on Age at Onset and Psychosis Outcomes in First-Episode Schizophrenia. Schizophr Bull. 2011 Mar 9. [Epub ahead of print] http://schizophreniabulletin.oxfordjournals.org/content/early/2011/03/09/schbul.sbq153.full.pdf+html
“Objective: Cannabis use is associated with a younger age at onset of psychosis, an indicator of poor prognosis, but better cognitive function, a positive prognostic indicator. We aimed to clarify the role of age at onset and cognition on outcomes in cannabis users with first-episode schizophrenia as well as the effect of cannabis dose and cessation of use……Conclusions: Cannabis use brings forward the onset of psychosis in people who otherwise have good prognostic features indicating that an early age at onset can be due to a toxic action of cannabis rather than an intrinsically more severe illness. Many patients abstain over time, but in those who persist, psychosis is more difficult to treat.”

Veen ND, Selten JP, van der Tweel I, Feller WG, Hoek HW, Kahn RS. Cannabis use and age at onset of schizophrenia. Am J Psychiatry. 2004 Mar;161(3):501-6. http://ajp.psychiatryonline.org/cgi/reprint/161/3/501
“The results indicate a strong association between use of cannabis and earlier age at first psychotic episode in male schizophrenia patients.”

Compton MT, Kelley ME, Ramsay CE, Pringle M, Goulding SM, Esterberg ML, Stewart T, Walker EF. Association of pre-onset cannabis, alcohol, and tobacco use with age at onset of prodrome and age at onset of psychosis in first-episode patients. Am J Psychiatry. 2009 Nov;166(11):1251-7. Epub 2009 Oct 1. http://ajp.psychiatryonlie.org/cgi/reprint/166/11/1251
“Whereas classifying participants according to maximum frequency of use prior to onset (none, ever, weekly, or daily) revealed no significant effects of cannabis or tobacco use on risk of (editor’s note: “timing of”) onset, analysis of change in frequency of use prior to
onset indicated that progression to daily cannabis and tobacco use was associated with an increased risk of onset of psychotic symptoms. Similar or even stronger effects were observed when onset of illness or prodromal symptoms was the outcome. A gender-by-daily-cannabis use interaction was observed; progression to daily use resulted in a much larger increased relative risk of onset of psychosis in females than in males.”

Myles N, Newall H, Compton MT, Curtis J, Nielssen O, Large M. The age at onset of psychosis and tobacco use: a systematic meta-analysis. Soc Psychiatry Psychiatr Epidemiol. 2011 Sep 8. [Epub ahead of print]
“Unlike cannabis use, tobacco use is not associated with an earlier onset of psychosis.”

Barnes TR, Mutsatsa SH, Hutton SB, Watt HC, Joyce EM. Comorbid substance use and age at onset of schizophrenia. Br J Psychiatry. 2006 Mar;188:237-42. http://bjp.rcpsych.org/content/188/3/237.full.pdf+html
“Alcohol misuse and any substance use (other than cannabis use) were not significant in relation to age at onset….. those patients in the sample who reported that they had used cannabis had an earlier age at onset of psychosis than other patients who did not report cannabis use but who shared the same profile with regard to the other variables (e.g. comparing men who reported alcohol misuse and use of both cannabis and other drugs with men who had the same characteristics apart from the fact that they had not used cannabis).”

Data from other cultures

Sarkar J, Murthy P, Singh SP. Psychiatric morbidity of cannabis abuse. Indian J Psychiatry. 2003 Jul;45(3):182-8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952166/pdf/IJPsy-45-182.pdf
“The paper evaluates the hypothesis that cannabis abuse is associated with a broad range of psychiatric disorders in India, an area with relatively high prevalence of cannabis use. Retrospective case-note review of all cases with cannabis related diagnosis over a 11 -year period, for subjects presenting to a tertiary psychiatric hospital in southern India was carried out. Information pertaining to sociodemographic, personal, social, substance-use related, psychiatric and treatment histories, was gathered. Standardized diagnoses were made according to Diagnostic Criteria for Research of the World Health Organization, on the basis of information available.Cannabis abuse is associated with
widespread psychiatric morbidity that spans the major categories of mental disorders under the ICD-10 system, although proportion of patients with psychotic disorders far outweighed those with non-psychotic disorders. Whilst paranoid psychoses were more prevalent, a significant number of patients with affective psychoses, particularly mania, was also noted.”

Rodrigo C, Welgama S, Gunawardana A, Maithripala C, Jayananda G, Rajapakse S. A retrospective analysis of cannabis use in a cohort of mentally ill patients in Sri Lanka and its implications on policy development. Subst Abuse Treat Prev Policy. 2010 Jul 8;5:16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910013/pdf/1747-597X-5-16.pdf
”BACKGROUND: Several epidemiological studies have shown that cannabis; the most widely used illegal drug in the world, is associated with schizophrenia spectrum disorders (SSD)……. CONCLUSIONS: Self reported LTC (editor’s note: life time cannabis) use was strongly associated with being diagnosed with SSD (editor’s note: schizophrenia spectrum disorders”.

Population study showing change in incidence rate in young when drug laws are eased

Ajdacic-Gross V, Lauber C, Warnke I, Haker H, Murray RM, Rössler W. Changing incidence of psychotic disorders among the young in Zurich. Schizophr Res. 2007 Sep;95(1-3):9-18. Epub 2007 Jul 16.
“There is controversy over whether the incidence rates of schizophrenia and psychotic disorders have changed in recent decades. To detect deviations from trends in incidence, we analysed admission data of patients with an ICD-8/9/10 diagnosis of psychotic disorders in the Canton Zurich / Switzerland, for the period 1977-2005. The data was derived from the central psychiatric register of the Canton Zurich. Ex-post forecasting with ARIMA (Autoregressive Integrated Moving Average) models was used to assess departures from existing trends. In addition, age-period-cohort analysis was applied to determine hidden birth cohort effects. First admission rates of patients with psychotic
disorders were constant in men and showed a downward trend in women. However, the rates in the youngest age groups showed a strong increase in the second half of the 1990’s. The trend reversal among the youngest age groups coincides with the increased
use of cannabis among young Swiss in the 1990’s.”

Estimates of how many men aged 20-40 would have to avoid regular marijuana use for one year in order to prevent one case of schizophrenia in that same year (but for number relevant to a 20 year avoidance of schizophrenia by avoiding regular marijuana use during
20 years, divide by 20):

Hickman M, Vickerman P, Macleod J, Lewis G, Zammit S, Kirkbride J, Jones P. If cannabis caused schizophrenia–how many cannabis users may need to be prevented in order to prevent one case of schizophrenia? England and Wales calculations. Addiction. 2009;104(11):1856-61.

“In men the annual mean NNP (number needed to prevent) for heavy cannabis and schizophrenia ranged from 2800 [90% confidence interval (CI) 2018–4530] in those aged 20–24 years to 4700 (90% CI 3114–8416) in those aged 35–39”.

Key studies interpreted to diminish the connection between marijuana and schizophrenia:

Proal AC, Fleming J, Galvez-Buccollini JA, Delisi LE. A controlled family study of cannabis users with and without psychosis. Schizophr Res. 2014 Jan;152(1):283-8.
“The results of the current study, both when analyzed using morbid risk and family frequency calculations, suggest that having an increased familial risk for schizophrenia is the underlying basis for schizophrenia in these samples and not the cannabis use. While cannabismay have an effect on theage of onset of schizophrenia it is unlikely to be the cause of illness.”

Rebuttal: Miller CL. Caution urged in interpreting a negative study of cannabis use and schizophrenia. Schizophr Res. 2014 Apr;154(1-3):119-20.
“The morbid risk reported for the relatives of the non-cannabis-using patients (Sample 3) was actually 1.4-fold higher than the cannabis using patients (Sample 4), but the study did not have enough power to statistically confirm or refute a less than 2-fold difference. An increase in sample size would be required to do so, and if the observed difference were to be confirmed, it would explain not only why the Sample 4 data fits poorly with a multigene/small environmental impact model but also would give weight to the premise that cannabis use significantly contributes to the development of this disease.”

Power RA, Verweij KJ, Zuhair M, Montgomery GW, Henders AK, Heath AC, Madden PA, Medland SE, Wray NR, Martin NG. Genetic predisposition to schizophrenia associated with increased use of cannabis. Mol Psychiatry. 2014 Jun 24. doi: 10.1038/mp.2014.51. [Epub ahead of print] http://emilkirkegaard.dk/en/wp-content/uploads/Genetic%20predisposition%20to%20schizophrenia%20associated%20with%20increased%20use%20of%20cannabis.pdf
“Our results show that to some extent the association between cannabis and schizophrenia is due to a shared genetic aetiology across common variants. They suggest that individuals with an increased genetic predisposition to schizophrenia are
both more likely to use cannabis and to use it in greater quantities.”

Rebuttal: Had this paper been titled “The causal genes for schizophrenia have been discovered” it would never have been published. In the absence of a consistent finding of genes of major effect size for schizophrenia, this study of inconsistently associated genes of low effect size is meaningless.

Buchy L, Perkins D, Woods SW, Liu L, Addington J. Impact of substance use on conversion to psychosis in youth at clinical high risk of psychosis. Schizophrenia Res 156 (2-3): 277–280.
“Results revealed that low use of alcohol, but neither cannabis use nor tobacco use at baseline, contributed to the prediction of psychosis in the CHR sample”.
Rebuttal: The study was small in size and the age range of their subjects at study onset was large (12 to 31) which included both subjects that had not reached the peak age of risk for schizophrenia even by the end of the study as well as subjects who were well past the peak age of onset of schizophrenia. The fact that the study screened out psychotic individuals was problematic for the latter group, in that those who were most vulnerable to the psychosis inducing effects of cannabis would already have converted to psychosis by that age.

Overview of Key Public Health Issues Regarding the Mental Health Effects of Marijuana

For the monetary cost of schizophrenia to the U.S. annually ($63 billion in 2002 dollars):

Wu EQ, Birnbaum HG, Shi L, Ball DE, Kessler RC, Moulis M, Aggarwal J. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry. 2005 Sep;66(9):1122-9.

For the trends in adolescent drug, alcohol and cigarette use, showing an upward tick in marijuana use as medical marijuana has become more prevalent, and that the mind-altering drug legal for adults (alcohol) is still more commonly used by teens than is marijuana:

Johnston, L. D., O’Malley, P. M., Bachman, J. G., & Schulenberg, J. E. (2012). Monitoring the Future national results on adolescent drug use: Overview of key findings, 2011. Ann Arbor, MI: Institute for Social Research, The University of Michigan.

For a summary of Sweden’s drug law experience:
Hallam C., 2010, Briefing paper 20, The Beckley Foundation: What Can We Learn from Sweden’s Drug Policy Experience? www.beckleyfoundation.org/pdf/BriefingPaper_20.pdf
“in the case of Sweden, the clear association between a restrictive drug policy and low levels of drug use is striking. In his foreword to the article on Sweden’s Successful Drug Policy, Antonio Maria Costa is frank enough to confess that, “It is my firm belief that the generally positive situation of Sweden is a result of the policy that has been applied to address the problem”.

For data showing the relationship between drug enforcement policies in Europe and drug use, such that Sweden has a zero tolerance policy on drugs and has one of the lowest rates of “last month use” in Europe (1%), 4-fold lower than the Netherlands and 7-fold lower than Spain and Italy, two countries that have liberalized their enforcement policies so that marijuana possession carries no substantive penalty.

European Monitoring Centre for Drugs and Addiction, 2012 Annual report
http://www.emcdda.europa.eu/attachements.cfm/att_190854_EN_TDAC12001ENC_.pdf

Source: Microsoft Word – 2015- Summary of literature on marijuana and psychosis.doc (momsstrong.org) January 2016

Filed under: Alcohol,Brain and Behaviour,Cannabis/Marijuana,Crime/Violence/Prison,Drug use-various effects,Effects of Drugs,Nicotine,Political Sector,Social Affairs :

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